Bone treatment systems and methods

ABSTRACT

The present disclosure relates to bone cement formulations that have an extended working time for use in vertebroplasty procedures and other osteoplasty procedures together with cement injectors that include energy delivery systems for on-demand control of cement viscosity and flow parameters. The bone cement formulations may include a liquid component having at least one monomer and a non-liquid component including polymer particles and benzoyl peroxide (BPO). The non-liquid component may be further configured to allow controlled exposure of the BPO to the liquid monomer so as to enable control of the viscosity of the bone cement composition.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 12/024,969, filed on Feb. 1, 2008. This application furtherclaims the benefit of priority under 35 U.S.C. §119(e) of U.S.Provisional Application Nos. 61/067,479, filed on Feb. 28, 2008,entitled Bone System Treatment Systems and Methods, 61/067,480, filed onFeb. 28, 2008, entitled Bone System Treatment Systems and Methods,61/124,336, filed on Apr. 16, 2008, entitled Bone Treatment Systems andMethods, 61/190,375 filed Aug. 28, 2008, entitled Bone Treatment Systemsand Methods, and 61/124,338 filed Apr. 16, 2008, entitled Bone TreatmentDevices and Methods, the entire contents of both of which are herebyincorporated by reference and should be considered a part of thisspecification.

BACKGROUND

1. Field

Embodiments of the present disclosure relate to bone cements and cementinjection systems, and in certain embodiments, systems and methods foron-demand control of bone cement viscosity for treating vertebralcompression fractures and for preventing cement extravasation.

2. Description of the Related Art

Osteoporotic fractures are prevalent in the elderly, with an annualestimate of 1.5 million fractures in the United States alone. Theseinclude 750,000 vertebral compression fractures (VCFs) and 250,000 hipfractures. The annual cost of osteoporotic fractures in the UnitedStates has been estimated at $13.8 billion. The prevalence of VCFs inwomen age 50 and older has been estimated at 26% and increases with age,reaching 40% among 80+ year-old women. Medical advances aimed at slowingor arresting bone loss from aging have not provided solutions to thisproblem, however. Further, the population affected grows steadily aslife expectancy increases. Osteoporosis affects the entire skeleton butmost commonly causes fractures in the spine and hip. Spinal or vertebralfractures also cause other serious side effects, with patients sufferingfrom loss of height, deformity and persistent pain which cansignificantly impair mobility and quality of life. Fracture pain usuallylasts 4 to 6 weeks, with intense pain at the fracture site. Chronic painoften occurs when one vertebral level is greatly collapsed or multiplelevels are collapsed.

Postmenopausal women are predisposed to fractures, such as in thevertebrae, due to a decrease in bone mineral density that accompaniespostmenopausal osteoporosis. Osteoporosis is a pathologic state thatliterally means “porous bones”. Skeletal bones are made up of a thickcortical shell and a strong inner meshwork, or cancellous bone, ofcollagen, calcium salts, and other minerals. Cancellous bone is similarto a honeycomb, with blood vessels and bone marrow in the spaces.Osteoporosis describes a condition of decreased bone mass that leads tofragile bones which are at an increased risk for fractures. In anosteoporosis bone, the sponge-like cancellous bone has pores or voidsthat increase in dimension making the bone very fragile. In young,healthy bone tissue, bone breakdown occurs continually as the result ofosteoclast activity, but the breakdown is balanced by new bone formationby osteoblasts. In an elderly patient, bone resorption can surpass boneformation thus resulting in deterioration of bone density. Osteoporosisoccurs largely without symptoms until a fracture occurs.

Vertebroplasty and kyphoplasty are recently developed techniques fortreating vertebral compression fractures. Percutaneous vertebroplastywas first reported by a French group in 1987 for the treatment ofpainful hemangiomas. In the 1990's, percutaneous vertebroplasty wasextended to indications including osteoporotic vertebral compressionfractures, traumatic compression fractures, and painful vertebralmetastasis. Vertebroplasty is the percutaneous injection of polymethylmethacrylate (PMMA) into a fractured vertebral body via a trocar andcannula. The targeted vertebrae are identified under fluoroscopy and aneedle is introduced into the vertebrae body, under fluoroscopiccontrol, to allow direct visualization. A bilateral transpedicular(through the pedicle of the vertebrae) approach is typical but theprocedure can be done unilaterally. The bilateral transpedicularapproach allows for more uniform PMMA infill of the vertebra.

In a bilateral approach, approximately 1 to 4 ml of PMMA or more is usedon each side of the vertebra. Since the PMMA needs to be forced into thecancellous bone, the techniques require high pressures and fairly lowviscosity cement. Since the cortical bone of the targeted vertebra mayhave a recent fracture, there is the potential of PMMA leakage. The PMMAcement contains radiopaque materials so that when injected under livefluoroscopy, cement localization and leakage can be observed. Thevisualization of PMMA injection and extravasation are critical to thetechnique, as the physician generally terminates PMMA injection whenleakage is observed. The cement is injected using syringes to allow thephysician manual control of injection pressure.

Balloon kyphoplasty is a modification of percutaneous vertebroplasty.Balloon kyphoplasty involves a preliminary step comprising thepercutaneous placement of an inflatable balloon tamp in the vertebralbody. Inflation of the balloon creates a cavity in the bone prior tocement injection. In balloon kyphoplasty, the PMMA cement can beinjected at a lower pressure into the collapsed vertebra since a cavityexists, as compared to conventional vertebroplasty. More recently, otherforms of kyphoplasty have been developed in which various tools are usedto create a pathway or cavity into which the bone cement is theninjected.

The principal indications for any form of vertebroplasty areosteoporotic vertebral collapse with debilitating pain. Radiography andcomputed tomography must be performed in the days preceding treatment todetermine the extent of vertebral collapse, the presence of epidural orforaminal stenosis caused by bone fragment retropulsion, the presence ofcortical destruction or fracture, and the visibility and degree ofinvolvement of the pedicles.

Leakage of PMMA during vertebroplasty can result in very seriouscomplications including compression of adjacent structures thatnecessitate emergency decompressive surgery. See “Anatomical andPathological Considerations in Percutaneous Vertebroplasty andKyphoplasty: A Reappraisal of the Vertebral Venous System”, Groen, R. etal, Spine Vol. 29, No. 13, pp 1465-1471 2004. Leakage or extravasationof PMMA is a critical issue and can be divided into paravertebralleakage, venous infiltration, epidural leakage and intradiscal leakage.The exothermic reaction of PMMA carries potential catastrophicconsequences if thermal damage were to extend to the dural sac, cord,and nerve roots. Surgical evacuation of leaked cement in the spinalcanal has been reported. It has been found that leakage of PMMA isrelated to various clinical factors such as the vertebral compressionpattern, and the extent of the cortical fracture, bone mineral density,the interval from injury to operation, the amount of PMMA injected andthe location of the injector tip. In one recent study, close to 50% ofvertebroplasty cases resulted in leakage of PMMA from the vertebralbodies. See Hyun-Woo Do et al, “The Analysis of PolymethylmethacrylateLeakage after Vertebroplasty for Vertebral Body Compression Fractures”,Jour. of Korean Neurosurg. Soc. Vol. 35, No. 5 (5/2004) pp. 478-82.

Another recent study was directed to the incidence of new VCFs adjacentto the vertebral bodies that were initially treated. Vertebroplastypatients often return with new pain caused by a new vertebral bodyfracture. Leakage of cement into an adjacent disc space duringvertebroplasty increases the risk of a new fracture of adjacentvertebral bodies. See Am. J. Neuroradiol. 2004 February; 25(2):175-80.The study found that 58% of vertebral bodies adjacent to a disc withcement leakage fractured during the follow-up period compared with 12%of vertebral bodies adjacent to a disc without cement leakage.

Another life-threatening complication of vertebroplasty is pulmonaryembolism. See Bernhard, J. et al, “Asymptomatic diffuse pulmonaryembolism caused by acrylic cement: an unusual complication ofpercutaneous vertebroplasty”, Ann. Rheum. Dis. 2003; 62:85-86. Thevapors from PMMA preparation and injection also are cause for concern.See Kirby, B, et al., “Acute bronchospasm due to exposure topolymethylmethacrylate vapors during percutaneous vertebroplasty”, Am.J. Roentgenol. 2003; 180: 543-544.

From the forgoing, then, there is a need to provide bone cements andmethods for use in treatment of vertebral compression fractures thatprovide a greater degree of control over introduction of cement and thatprovide better outcomes.

SUMMARY

In an embodiment, a bone cement composition is provided. The compositioncomprises a liquid component and a non-liquid component that, uponmixing, provide a polymerizable bone cement composition. The liquidcomponent comprises at least one monomer and the non-liquid componentcomprises at least a polymer and an initiator. The non-liquid componentis configured to allow controlled exposure of the initiator to theliquid monomer so as to control the viscosity of the bone cementcomposition over a working time in which the cement is injected intobone.

In another embodiment, a bone cement composition is provided. The bonecement composition comprises a monomer component and a polymercomponent. The polymer component comprises a first volume of polymerparticles and a second volume of polymer particles. The first volume ofpolymer particles comprises greater than about 0.5 wt. % BPO and thesecond volume of polymer particles comprises less than about 0.5 wt. %BPO, on the basis of the total weight of the polymer component.

In a further embodiment, a bone cement composition is provided. The bonecement composition comprises a monomer component and a polymercomponent. The polymer component comprises particles of at least onepolymer and about 0.2 to 3 wt. % benzoyl peroxide (BPO). The BPO isprovided in at least two of the following configurations: as a surfacecoating upon at least a portion of the polymer particles, one or morelayers within the interior of the polymer particles, as BPOmicrocapsules and BPO particles. In certain embodiments, the BPOparticles may be integrated into the polymer particles. In otherembodiments, the BPO particles may not be integrated into the polymerparticles. In further embodiments, the BPO microcapsules may beintegrated into the polymer particles.

In an embodiment, a method of treating bone is provided. The methodcomprises mixing a liquid component and a non-liquid component toprovide a polymerizable bone cement composition. The liquid componentcomprises at least one monomer and the non-liquid component comprisespolymer particles and benzoyl peroxide (BPO). The non-liquid componentis configured to control the amount of BPO that is exposed to the liquidcomponent as a function of time during polymerization of the bone cementcomposition.

In a further embodiment, a bone cement composition is provided. The bonecement composition comprises a powder component and a liquid component.The powder component comprises about 45%-55 wt. % polymethylmethacrylatepolymer (PMMA), about 25-35 wt. % Zirconium Dioxide or Barium Sulfate,and benzoyl peroxide (BPO), where the amounts of each of the powdercomponents are based upon the total weight of the powder component. Theliquid component comprises about 98.0-99.9 wt. % Methylmethacrylate(MMA), about 0.15-0.95 wt. % N, N-dimethyl-p-toluidine (DMPT), and about30-150 ppm hydroquinone (HQ), where the amounts of the liquid componentsare on the basis of the total weight of the liquid component.

In another embodiment, a bone cement is provided. The bone cementcomprises a first monomer-carrying component and a secondpolymer-carrying component, wherein post-mixing the mixture of the firstand second components is characterized, after an initial exposureperiod, as having a time-viscosity curve slope of less than or equal toabout 200 Pa·s/minute until the mixture reaching a viscosity of about2000 Pa·s.

In an additional embodiment, a bone cement is provided. The bone cementcomprises a first monomer-carrying component and a secondpolymer-carrying component, wherein post-mixing the mixture ischaracterized by a time-viscosity curve slope of less than or equal toabout 200 Pa·s/minute immediately before the mixture reaches a viscosityof about 1500 Pa·s.

In a further embodiment, a bone cement is provided. The bone cementcomprises a first monomer-carrying component and a secondpolymer-carrying component, wherein post-mixing the mixture of the firstand second components is characterized, after an initial exposureperiod, as having a time-viscosity curve slope of less than or equal toabout 1500 Pa·s at about 25 minutes post-mixing.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to better understand the embodiments of the present disclosureand to see how it may be carried out in practice, some preferredembodiments are next described, by way of non-limiting examples only,with reference to the accompanying drawings, in which like referencecharacters denote corresponding features consistently throughout similarembodiments in the attached drawings.

FIG. 1 is a schematic, perspective view of a bone cement injectionsystem in accordance with one embodiment of the present disclosure;

FIG. 2 is a schematic, exploded side view of the system of FIG. 1,illustrating the bone cement injection components de-mated from oneanother;

FIG. 3 is a schematic illustration of one embodiment of a thermalemitter component of the system of FIGS. 1 and 2;

FIG. 4 is a schematic, exploded perspective view of a force applicationand amplification component of the system of FIGS. 1-2 in combinationwith an embodiment of a pressurization mechanism and in communicationwith an energy source and a controller;

FIG. 5 is an enlarged, assembly view of an embodiment of thepressurization mechanism of the system of FIG. 4;

FIG. 6 is a perspective view of components of the system of FIGS. 1-5with a perspective view of an embodiment of an energy source andcontroller.

FIG. 7 is chart indicating a time-viscosity curve for a prior art PMMAbone cement.

FIG. 8A is diagram indicating the method of utilizing applied energy andan energy-delivery algorithm to accelerate the polymerization of a PMMAbone cement to provide a selected time-viscosity curve.

FIG. 8B is chart indicating a modified time-viscosity curve for a PMMAbone cement of FIG. 7 when modified by applied energy from a thermalenergy emitter and a selected energy-delivery algorithm according to anembodiment of the present disclosure.

FIGS. 8C and 8D are images of PMMA bone cement exiting an injectorwithout applied energy and the same PMMA bone cement exiting an injectoras modified by applied energy according to one embodiment ofenergy-delivery algorithm.

FIG. 9 is chart indicating another modified time-viscosity curve for thePMMA bone cement of FIGS. 7 and 8A when modified by applied energy usingan alternative energy-delivery algorithm.

FIG. 10 is chart indicating time-viscosity curves for an embodiment ofPMMA bone cement as in FIG. 8A at different ambient temperatures.

FIG. 11 is a view of another embodiment of a bone cement injectionsystems with components de-mated from one another where the systemincluded first and second thermal energy emitters.

FIG. 12 is a plot illustrating setting time as a function of theconcentration of BPO and DMPT present within embodiments of a bonecement composition.

FIG. 13 is a plot illustrating the temperature-time behavior ofembodiments of the bone cement composition under conditions where thecomposition is and is not heated.

FIG. 14 is a plot illustrating the viscosity-time behavior ofembodiments of the bone cement composition heated to temperaturesranging between about 25° C. to 55° C.

FIG. 15 is chart indicating time-viscosity curves for two embodiments ofPMMA bone cement of this disclosure as well as other commerciallyavailable PMMA bone cements.

FIG. 16 is a schematic view of polymer beads of an embodiment of a bonecement of the present disclosure.

FIG. 17 is a schematic view of polymer beads of another bone cementembodiment of the present disclosure.

FIG. 18 is a schematic view of polymer beads of a further embodiment ofa bone cement of the present disclosure.

FIG. 19 is a schematic view of polymer beads of an additional bonecement embodiment of the present disclosure.

FIG. 20 is a schematic view of polymer beads of another bone cementembodiment of the present disclosure.

FIG. 21 is a chart indicating free indicator (BPO) available to beexposed to monomer over a post-mixing interval of a cement of thepresent disclosure showing a first positive slope followed by asubstantially constant BPO availability.

FIG. 22 is another chart indicating free initiator (BPO) available to beexposed to monomer over a post-mixing interval of a cement of thepresent disclosure.

FIG. 23 is a chart indicating initiator (BPO) availability over apost-mixing interval of another cement.

FIG. 24 is a schematic view of polymer beads of another bone cementembodiment of the present disclosure.

FIG. 25 is a chart indicating a time viscosity curve of a cement of FIG.23 over a post-mixing interval.

DETAILED DESCRIPTION

For purposes of understanding the principles of the embodiments of thepresent disclosure, reference will now be made to the embodimentsillustrated in the drawings and accompanying text. As background, avertebroplasty procedure using embodiments of the present disclosure mayintroduce the injector of FIGS. 1-2 through a pedicle of a vertebra, orin a parapedicular approach, for accessing the osteoporotic cancellousbone. The initial aspects of the procedure are similar to percutaneousvertebroplasty, where the patient is placed in a prone position on anoperating table. The patient is typically under conscious sedation,although general anesthesia is an alternative. The physician injects alocal anesthetic (e.g., about 1% Lidocaine) into the region overlyingthe targeted pedicle or pedicles, as well as the periosteum of thepedicle(s). Thereafter, the physician may use a scalpel to make anapproximately 1 to 5 mm skin incision over each targeted pedicle.Thereafter, the bone cement injector is advanced through the pedicleinto the anterior region of the vertebral body, which typically is theregion of greatest compression and fracture. The physician confirms theintroducer path posterior to the pedicle, through the pedicle and withinthe vertebral body, by anteroposterior and lateral X-Ray projectionfluoroscopic views. The introduction of infill material as describedbelow can be imaged several times, or continuously, during the treatmentdepending on the imaging method.

The terms “bone cement”, “bone fill”, “bone fill material”, “infillmaterial”, and “infill composition” include their ordinary meaning asknown to those skilled in the art and may include any material forinfilling a bone that includes an in-situ hardenable or settable cementand compositions that can be infused with such a hardenable cement. Thefill material also can include other fillers, such as filaments,microspheres, powders, granular elements, flakes, chips, tubules and thelike, autograft or allograft materials, as well as other chemicals,pharmacological agents, or other bioactive agents.

The term “flowable material” includes its ordinary meaning as known tothose skilled in the art and may include a material continuum that isunable to withstand any static shear stress and responds with asubstantially irrecoverable flow (e.g., a fluid), unlike an elasticmaterial or elastomer that responds to shear stress with a recoverabledeformation. Flowable materials may include fill materials or compositesthat may include a first, fluid component alone or in combination withan second, elastic, or inelastic material component that responds tostress with a flow, no matter the proportions of the first and secondcomponent. It may be understood that the above shear test does not applyto the second component alone.

The terms “substantially” or “substantial” include their ordinarymeaning as known to those skilled in the art and may mean largely butnot entirely. For example, “substantially” and “substantial” may meanabout 50% to about 99.999%, about 80% to about 99.999% or about 90% toabout 99.999%.

The term “vertebroplasty” includes its ordinary meaning as known tothose skilled in the art and may include any procedure where fillmaterial is delivered into the interior of a vertebra.

The term “osteoplasty” includes its ordinary meaning as known to thoseskilled in the art and may include any procedure where a fill materialis delivered into the interior of a bone.

In FIG. 1, an embodiment of a system 10 is shown that includes a firstcomponent or bone cement injector 100 may extend into the cancellousbone of a vertebra, and a second component or cement activationcomponent 105 which includes an emitter 110 for applying energy to bonecement. The first and second components 100 and 105 may include a flowpassageway or channel 112 extending therethrough for delivering flowablebone cement into a bone. The bone cement injector component 100 and thecement activation component 105 can be integrated into a unitary deviceor can be de-mateable, as shown in FIG. 2, by a mechanism such as athreaded portion 113 and a rotatable screw-on fitting 114. As can beseen in FIGS. 1 and 2, a source of bone cement in the form of asyringe-type body 115 is also coupleable to the system by use of athreaded fitting 116.

Referring to FIG. 2, the bone cement injector 100 may include a proximalend 118 and a distal end 120 with at least one flow outlet 122 thereinto direct a flow of cement into a bone. The extension portion 124 of theinjector 100 can be made of any suitable metal or plastic sleeve withflow channel 112 extending therethrough to the flow outlet 122. The flowoutlet 122 may be present as a side port to direct cement flowtransverse relative to the axis 125 of extension portion 124 or,alternatively, can be positioned at the distal termination of extensionportion 124 in order to direct cement flows distally. In anotherembodiment (not shown) the extension portion 124 can include first andsecond concentric sleeves that are positioned so as to be rotatedrelative to one another to align or misalign respective first and secondflow outlets to allow selectively directed cements flow to be more orless axial relative to axis 125 of extension portion 124.

Now turning to the cut-away view of FIG. 2, it can be seen that secondcomponent 105 includes a handle portion that carries an emitter 110 forapplying thermal energy to a cement flow within the flow channel 112that extends through the emitter 110. As will be described furtherbelow, the emitter 110 may apply thermal energy to bone cement 130delivered from chamber 132 of source 115 to flow through the emitter 110to therein to cause the viscosity of the cement to increase to aselected, higher viscosity value as the cement exits the injector flowoutlet 122 into bone. The controlled application of energy to bonecement 130 may enable the physician to select a setting rate for thecement to reach a selected polymerization endpoint as the cement isbeing introduced into the vertebra, thus allowing a high viscosity thatwill be prevent unwanted cement extravasation.

Referring to FIGS. 2 and 3, in one embodiment, the thermal energyemitter 110 may be coupled to an electrical source 140 and controller145 by an electrical connector 146 and a cable 148. In FIG. 2, it can beseen that electrical leads 149 a and 149 b may be coupled with connector146 and extend to the emitter 110. As can be seen in FIG. 3, oneembodiment of thermal energy emitter 110 has a wall portion 150 thatincludes a polymeric positive temperature coefficient of resistance(PTCR) material with spaced apart interlaced surface electrodes 155A and155B as described in co-pending Provisional Application No. 60/907,469filed Apr. 3, 2007 titled Bone Treatment Systems and Methods. In thisembodiment, the thermal emitter 110 and wall 150 thereof may resistivelyheat to thereby cause controlled thermal effects in bone cement 130flowing therethrough. It may be appreciated that FIG. 3 is a schematicrepresentation of one embodiment of thermal energy emitter 110 which canhave any elongated or truncated shape or geometry, tapered ornon-tapered form, or include the wall of a collapsible thin-wallelement. Further, the positive (+) and negative (−) polarity electrodes155A and 155B can have any spaced apart arrangement, for exampleradially spaced apart, helically spaced apart, axially spaced apart orany combination thereof. This resistively heated PTCR material of theemitter 110 may further generate a signal that indicates flow rate asdescribed in Provisional Application No. 60/907,469 which in turn can beutilized by controller 145 to modulate energy applied to the bone cementtherein, and/or modulate the flow rate of cement 130, which can bedriven by a motor or stored energy mechanism. In another embodiment, theemitter can be any non-PTCR resistive heater such as a resistive coilheater.

In other embodiments, the thermal energy emitter 110 can include a PTCRconstant temperature heater as described above or may include one ormore of a resistive heater, a fiber optic emitter, a light channel, anultrasound transducer, an electrode and an antenna. Accordingly in anysuch embodiment, the energy source 140 can include at least one of avoltage source, a radiofrequency source, an electromagnetic energysource, a non-coherent light source, a laser source, an LED source, amicrowave source, a magnetic source and an ultrasound source that isoperatively coupled to the emitter 110.

Referring FIG. 2, it can be understood that a pressure mechanism 190 iscoupleable to the bone cement source or syringe 115 for driving the bonecement 130 through the system 10. The pressure 190 can include anysuitable manual drive system or an automated drive system such as anypump, screw drive, pneumatic drive, hydraulic drive, cable drive or thelike. Such automated drive systems may be coupled to controller 145 tomodulate the flow rate of cement through the system.

In one embodiment, shown in FIGS. 4-6, the system 10 may further includea hydraulic system 162 with a fitting 163 that may detachably couple tofitting 164 of the bone cement source 115. In this embodiment, the bonecement source 115 may include a syringe body with cement-carrying boreor chamber 165 that carries a pre-polymerized, partially polymerized, orrecently-mixed bone cement 130 therein. The hydraulic system 162 mayfurther include a rigid plunger or actuator member 175 with o-ring orrubber head 176 that may move in chamber 165 so as to push the cement130 through the syringe chamber 165 and the flow channel 112 in thesystem 100.

Still referring to FIGS. 4-6, a force application and amplificationcomponent 180 of the hydraulic system 162 may be reversibly couple tothe bone cement source 115, where the force application andamplification component 180 includes a body 182 with pressurizable boreor chamber 185 therein that slidably receives the proximal end 186 ofthe actuator member 175. The proximal end 186 of actuator member 175 mayinclude an o-ring or gasket 187 so that the bore 185 can be pressurizedwith flow media 188 by the pressure source 190 in order to drive theactuator member 170 distally to thereby displace bone cement 130 fromthe chamber 132 in the cement source or syringe 115. In one embodiment,illustrated in FIG. 5, the surface area of an interface 200 between theactuator member 175 and pressurized flow media 188 may be larger thanthe surface area of an interface 200′ between the actuator member 175and the bone cement 130 so as to thereby provide pressure amplificationbetween the pressurizable chamber 185 and chamber 132 of the cementsource or syringe. In one embodiment, as indicated in FIGS. 4 and 5, thesurface area of interface 200 may be at least about 150% of the surfacearea of interface 200′, at least about 200% of the surface area ofinterface 200′, at least about 250% of the surface area of interface200′ and at least about 300% of the surface area of interface 200′.

Referring to FIGS. 4 and 5, in one embodiment, the force application andamplification component 188 may be employed in the following manner. Ina first operation, a bone fill material injector with a displaceable,non-fluid actuator component intermediate a first fluid chamber and asecond cement or fill-carrying chamber may be provided. In a secondoperation, a flow of flow media may be provided into the first fluidchamber at a first pressure to thereby displace the actuator componentto impinge on and eject bone cement or fill at a higher second pressurefrom the second chamber into a vertebra. In a non-limiting example, asecond pressure may be provided in the cement-carrying chamber 165 thatis greater than the first pressure in the pressurizable chamber.

In one embodiment, the second pressure may be at least about 50% higherthan the first pressure in the pressurizable chamber 185. In anotherembodiment, the second pressure may be at least about 75% higher thatthe first pressure in the pressurizable chamber 185. In anotherembodiment, the second pressure may be at least about 100% higher thatthe first pressure in the pressurizable chamber 185. In anotherembodiment, the second pressure may be at least about 200% higher thatthe first pressure in the pressurizable chamber 185. In anotherembodiment, the second pressure may be at least about 300% higher thatthe first pressure in the pressurizable chamber 185.

Referring to FIGS. 5 and 6, one embodiment of pressurizing mechanism forproviding pressure to the force application and amplification component180 may include a pneumatic or hydraulic line 205 that extends topressure mechanism 190, such as a syringe pump 210, which is manuallydriven or motor-driven as is known in the art. In one embodiment, asshown in FIG. 6, the syringe pump 210 may be driven by an electric motor211 operatively coupled to controller 145 to allow modulation of thepressure or driving force in combination with the control of energydelivery by emitter 110 from energy source 140.

It may be appreciated that the pressurizing mechanism or pressure source210 can include any type of mechanism or pump known in the art toactuate the actuator member 175 to move the bone cement in chamber 165.For example, a suitable mechanism can include a piezoelectric elementfor pumping fluid, an ultrasonic pump element, a compressed air systemfor creating pressure, a compressed gas cartridge for creating pressure,an electromagnetic pump for creating pressure, an air-hammer system forcreating pressure, a mechanism for capturing forces from a phase changein a fluid media, a spring mechanism that may releaseably store energy,a spring mechanism and a ratchet, a fluid flow system and a valve, ascrew pump, a peristaltic pump, a diaphragm pump, rotodynamic pumps,positive displacement pumps, and combinations thereof.

Referring to FIG. 6, another feature of embodiments of the presentdisclosure is a remote switch 212 for actuating the pressure mechanism190. In one embodiment, a cable 214 extends from the controller 145 sothat the physician can stand outside of the radiation field created byany imaging system used while treating a vertebra or other bonetreatment site. In another embodiment, the switch 212 can be wirelesslyconnected to the system as is known in the art. In another embodiment(not shown), the elongated cable 214 and switch 212 can be directlycoupled to the injector 100 or other component of the system 10.

Now turning to FIGS. 7, 8A and 8B, the figures illustrate certainembodiments of a method of the present disclosure where the controlledapplication of energy to a bone cement 130 provides a bone cement with acontrolled, on-demand increased viscosity and a controlled set timecompared to prior art bone cements. FIG. 7 depicts a prior art bonecement known in the art, such as a PMMA bone cement, that has atime-viscosity curve 240 where the cement substantially hardens or cureswithin about 8 to 10 minutes post-mixing. On the horizontal axis ofFIGS. 7 and 8A, the time point zero indicates the time at which themixing of bone cement precursors, such as monomer and polymercomponents, is approximately completed.

As can be seen in time-viscosity curve 240 for the prior art bone cementof FIG. 7, the cement increases in viscosity from about 500 Pa·s toabout 750 Pa·s from time zero to about 6 minutes post-mixing.Thereafter, the viscosity of the prior art bone cement increases veryrapidly over the time interval from about 6 minutes to 8 minutespost-mixing to a viscosity greater than 4000 Pa·s. A prior art bonecement having the time-viscosity curve of FIG. 7 may be considered tohave a fairly high viscosity for injection in the range of about 500Pa·s. At this viscosity range, however, the bone cement can still haveflow characteristics that result in extravasation.

Still referring to FIG. 7, it can be understood that the curing reactionof the bone cement involves an exothermic chemical reaction thatinitiates a polymerization process that is dictated, at least in part,by the composition of the bone cement precursors, such as one or more ofa PMMA polymer, monomer, and initiator. FIG. 7 indicates the exothermiccuring reaction over time as a gradation, where, the lighter gradationregion indicates a lesser degree of chemical reaction and heat and thedarker gradation region indicates a greater degree of chemical reactionand heat leading to more rapid polymerization of the bone cementprecursors.

Now turning FIG. 8A, the block diagram illustrates an embodiment of amethod of utilizing applied energy and an energy-delivery algorithm toaccelerate the polymerization of a PMMA bone cement to provide aselected time-viscosity curve as shown in FIG. 8B. In FIGS. 7 and 8B, itcan be seen that the time-viscosity curve 250 of one embodiment of abone cement can have an initial viscosity is in the range of about 750Pa·s at about time zero post-mixing and thereafter the viscosityincreases in a more linear manner over about 10 to 14 minutespost-mixing than prior art bone cements. This embodiment of bone cementmay include a PMMA cement composition that provides a time-viscositycurve as in FIGS. 7 and 8B, as described in U.S. Provisional ApplicationNo. 60/899,487 filed on Feb. 5, 2007, titled Bone Treatment Systems andMethods, and U.S. application Ser. No. 12/024,969, filed on Feb. 5,2008, titled Bone Treatment Systems and Methods, which are eachincorporated herein by this reference in their entirety. As can be seenin FIG. 8B, the bone cement 130, or more particularly, the mixing of thecement precursors includes a first curing reaction source for curing thebone cement as described above and results in the predeterminedexothermic curing reaction post-mixing that is indicated by thegradations of reaction under the time-viscosity curve 250.

Still referring to FIG. 8B, the chart illustrates the PMMA bone cementwith time-viscosity curve 250 together with the modified time-viscositycurve 260. The modified time-viscosity curve may be provided by theapplication of energy employing an embodiment of the system 10 of thepresent disclosure, as depicted in FIGS. 1 and 4-6. In other words, FIG.8B illustrates one embodiment of the present disclosure, where the bonecement 130 undergoes a curing process (i.e., the time-viscosity curve250) owing to self-heating of the composition as components of the bonecement composition react with each other. This curing process may befurther influenced by the applied energy from energy source 140,controller 145 and emitter 110 to provide the modified time-viscositycurve 260 for cement injection into a bone in order to preventextravasation.

As can be understood from FIG. 8B, the modulation of applied energy overtime from the second curing source or emitter 110, indicatedschematically at energy applications Q, Q′, and Q″, can be provided tocomplement the thermal energy generated by the exothermic reaction ofthe bone cement components in order to provide a substantially constantcement viscosity over a selected working time. This aspect ofembodiments of the present disclosure allows, for the first time, theprovision of bone cements having a controlled, and substantiallyconstant, viscosity that is selected so as to inhibit extravasation.

The bone cement 130 and system 10 of embodiments of the presentdisclosure are therefore notable in that a typical treatment of avertebral compression fracture requires cement injection over a periodof several minutes, for example from about 2 to 10 minutes or about 2 to6 minutes, or about 2 to 4 minutes. The physician typically injects asmall amount of bone cement, for example, about 1 of 2 cc's, then pausescement injection for the purpose of imaging the injected cement to checkfor extravasation, then injecting additional cement and then imaging,etc. The steps of injection and imaging may be repeated from about 2 to10 times or more, where the complete treatment interval can take about 4to 6 minutes or more. It can be easily understood that a cement with aworking time of at least about 5-6 minutes is needed for a typicaltreatment of a VCF, otherwise the first batch of cement may be tooadvanced in the curing process (see FIG. 7) and a second batch of cementmay need to be mixed. In embodiments of the cement 130 and system 10 ofthe present disclosure, however, as indicated in FIG. 8B, the cementviscosity can be approximately constant, thus providing a very longworking time of about 8-10 minutes.

It should be appreciated that, in the chart of FIG. 8B, the contributionto bone cement curing owing to self-heating of the bone cementcomposition and applied energy are indicated by shaded areas belowcurves 250 and 260. This graphic representation, however, is forconceptual purposes only, as the vertical axis measures viscosity inPa·s. The actual applied energy, indicated at Q to Q″, may be determinedby analysis of the actual polymerization reaction time of a selectedbone cement composition at a selected ambient temperature andatmospheric pressure.

Thus, in one embodiment of the present disclosure, the bone cementsystem includes: a first energy source and a second energy source,different from one another, that facilitate a curing reaction occurringwithin a bone cement. The first energy source includes heat generated byan exothermic curing reaction resulting from mixture of bone cementprecursor components. The second energy source includes thermal energyintroduced into the bone cement by a thermal energy emitter 110 that mayprovide a selected amount of energy to the bone cement. The systemfurther includes a controller 145 that may modulate the thermal energyprovided to the bone cement composition by the thermal energy emitter110. In this manner, the curing reaction of the bone cement compositionmay be controlled over a selected working time. It can be understoodfrom U.S. Provisional Application No. 60/899,487 and U.S. applicationSer. No. 12/024,969, that PMMA cement compositions can be created toprovide highly-extended working times.

The benefits of such viscosity control may be observed in FIGS. 8C and8D, which, respectively, are images of a PMMA bone cement exiting aninjector without applied energy and the same PMMA bone cement exiting aninjector as modified by applied energy according to one embodiment ofenergy-delivery algorithm. The bone cement emerging from the injectorwithout the benefit of applied energy is of relatively low viscosity, asevidenced by the ease with which the bone cement is deformed by theforce of gravity. Such behavior indicates the bone cement of FIG. 8C maybe prone to extravasation. In contrast, the bone cement modified byapplied energy of high viscosity, as evidenced by its accumulation aboutthe end of the injector. Such behavior indicates that the bone cement ofFIG. 8D is not prone to extravasation.

In another embodiment of the present disclosure, referred to FIG. 9, thecontroller 145 may also allow the physician to select an energy-deliveryalgorithm in the controller 145 to increase and decrease the cementviscosity as the cement exits the injector following the application ofenergy to the cement flow. Beneficially, such algorithms may providesubstantially automated control of the application of energy to thecomposition by the system 10.

Thus, in another embodiment, a bone treatment system 10 may be providedthat employs algorithms for modulating energy applied to the bone cementsystem 130. The bone treatment system 130 may include a bone cementinjector system, a thermal energy emitter 110 that may deliver energy toa flow of bone cement through the injector system, and a controller. Thecontroller 145 may include hardware and/or software for implementing oneor more algorithms for modulating applied energy from the emitter 110 toa bone cement flow. The energy-delivery algorithms may be furtheremployed to increase the applied energy from about zero to a selectedvalue at a rate that inhibits vaporization of at least a portion of amonomer portion of the bone cement 130.

In another embodiment of the present disclosure, the controller 145 mayenable a physician to select a bone cement viscosity using a selectormechanism operatively connected to the controller 145. In certainembodiments, the selector mechanism may cause the controller 145 toinitiate one or more of the energy-delivery algorithms. In oneembodiment, the physician can select among a plurality of substantiallyconstant viscosities that can be delivered over the working time.Examples of ranges of such viscosities may include less than about 1,000Pa·s and greater than about 1,500 Pa·s. It should be appreciated that,in certain embodiments, from two to six or more such selections may beenabled by the controller 145, with each selection being a viscosityrange useful for a particular purpose, such as about 1,000 Pa·s fortreating more dense bone when extravasation is of a lesser concern, orbetween about 4,000 Pa·s and 6,000 Pa·s in a treatment of a vertebralfracture to prevent extravasation and to apply forces to vertebralendplates to reduce the fracture.

In order to facilitate energy application to the bone cement compositionin a repeatable manner, the system 10 may further include a temperaturesensor 272 that is disposed in a mixing device or assembly 275. Themixing assembly 275 may include any container that receives bone cementprecursors for mixing before placement of the mixed cement in the bonecement source 115 (see FIG. 6). In certain embodiments, the temperaturesensor 272 may be placed in the cement mixing assembly 275 becausecement may be stored in a hospital in an environment having a lower orhigher temperature than the operating room, which may affect thetime-viscosity curve of the cement. The temperature sensor 272 can beoperatively coupled to the controller 145 by a cable or a wirelesstransmitter system. In certain embodiments, the sensor 272 may beunitary with the mixing assembly 175 and disposable. In alternativeembodiments, the sensor 272 can be reusable and detachable from themixing assembly 275.

In another embodiment, still referring to FIG. 6, a temperature sensor276 may be operatively connected to one or more packages 280 of the bonecement precursors to thereby indicate the actual temperature of thecement precursor(s) prior to mixing. Such a temperature sensor 276 mayindicate the stored temperature and/or the length of time that suchcement precursors have been in the operating room when compared toambient room temperature measured by sensor 270 in the controller 145.This sensor 276 can include one or more temperature sensors that mayinclude, but are not limited to, thermocouples, or thermochromic inks.The temperature sensors 276 may be further disposed on the surface ofthe bone cement package 280, allowing for visual identification of thetemperature of the cement precursors. In this manner, a doctor ortechnician may read the temperature of the package 280 and manuallyinput this temperature into the controller 145 to enable automaticadjustment of the energy delivery algorithms of embodiments of thecontroller 145. In another embodiment, referring back to FIG. 4, atleast one temperature sensor 282 can be located in cement source 115 ofthe system and/or in a distal portion of the injector component 100 formonitoring cement temperature in a cement flow within the system 10.

Thus, in another embodiment, a bone treatment system may include a bonecement injector system 10 that includes a thermal energy emitter 110that may deliver energy to a bone cement within the injector system, acontroller 145 that may modulate applied energy from the emitter tocontrol a curing reaction of the cement, and a sensor system operativelycoupled to the injector system 100 for measuring an operationalparameter of bone cement 130 within the system 10. In FIG. 6, in oneembodiment, it can be seen that a sensor of the sensor system mayinclude a temperature sensor, indicated at 270, which is disposed incontroller assembly 145. The temperature sensor 270 of the controllerassembly 145 may allow for input of control algorithms into the system10 for modulating applied energy from the emitter 110 that are dependenton ambient air temperature in the operating room environment. Suchcontrol algorithms may be of significant utility, as the ambienttemperature of an operating room may affect the time-viscosity curve ofan exothermic PMMA-based bone cement.

In another embodiment, the bone cement system 10, and more particularly,the cement mixing assembly 275 of FIG. 6 may include a sensor, switch,or indication mechanism 285 for indicating an approximate time ofinitiation of bone cement mixing. Such a sensor or indication mechanism285 can include any manually-actuated mechanism coupled to thecontroller 145, a mechanism that senses the disposition of the cementprecursors in the mixing assembly or the actuation of any moveablemixing component of the assembly, and combinations thereof. The system10 and controller 145 may, in this manner, provide one or more ofvisual, aural, and/or tactile signals indicating that a selected mixingtime interval has been reached. This signal may enable consistentmeasurement of the time at which mixing of the bone cement is completed,also referred to as the zero post-mixing time, such that the viscosityat this time may be similar in all cases. Beneficially, by precise,consistent measurement of the zero post-mixing time, energy may beproperly applied as described above. The system 10 also can include asensor, switch or indication mechanism 288 that indicates thetermination of bone cement mixing, and thus time zero on atime-viscosity curve as in FIG. 9, which may be used for setting thealgorithms in the controller 145 for controlling applied energy and thecement flow rate.

In another embodiment, the bone cement system 10 may include a sensorthat measures and indicates the bone cement flow rate within the flowpassageway in the injector system 100. In the embodiment of FIG. 6, themotor drive system 211 may drive the cement via the hydraulic system 162at a substantially constant rate through the injector and emitter 110. Asensor 290 may be operatively coupled to the motor drive which canmeasure the force being applied by the drive to the cause the desiredcement flow through the system 10, which can in turn be used to senseany tendency for a slow-down in the desired flow rate, for example dueto an unanticipated increase in viscosity of the bone cement in thesystem 10. Upon such sensing, the controller 145 can increase the flowrate or decrease the applied energy from emitter 110 to allow a selectedcement viscosity and flow rate from the injector 100 into bone to bemaintained.

Embodiments of such bone cements 130, in combination with the system 10of the embodiments of the present disclosure, may thus allow forselected working times. Examples of such working times may include, butare not limited to, at least about 6 minutes, at least about 8 minutes,at least about 10 minutes, at least about 12 minutes, at least about 14minutes, at least about 16 minutes, at least about 18 minutes, at leastabout 20 minutes, and at least about 25 minutes.

In one embodiment, the bone treatment system may include: a first andsecond energy source for causing a controlled curing reaction in a bonecement. The first source may include an exothermic curing reaction whichoccurs in response to mixing cement precursor components. The secondsource may include a thermal energy emitter capable of applying energyto the bone cement in order to vary an exothermic curing reaction of thebone cement. The system may further include a controller capable ofmodulating the applied energy from the emitter to thereby control theexothermic curing reaction over a selected working time. The controllermay be capable of modulating applied energy to provide a selected bonecement viscosity over a working time of at least about 2 minutes, atleast about 4 minutes, at least about 6 minutes, at least about 8minutes, at least about 10 minutes, at least about 12 minutes, at leastabout 14 minutes, at least about 16 minutes, at least about 18 minutes,at least about 20 minutes, and at least about 25 minutes.

In further embodiments the control system 10 may allow for applicationof energy to a bone cement so as to provide a bone cement that possessesa selected cement viscosity range as it exits the injector outlet 122over the selected working time. In certain embodiments, the selectedviscosity range may include, but is not limited to, about 600 Pa·s,about 800 Pa·s, about 1000 Pa·s, about 1200 Pa·s, about 1400 Pa·s, about1600 Pa·s, about 1800 Pa·s, about 2000 Pa·s, about 2500 Pa·s, about 3000Pa·s and about 4000 Pa·s.

Thus, in another embodiment of the present disclosure, a method ofpreparing a curable bone cement for injection into a vertebra may beprovided. The method can include: mixing bone cement precursors so as toenable a curing reaction to take place in the bone cement and applyingenergy to the bone cement from an external source so as to provideenergy to the bone cement. The energy applied from the external sourcemay be controlled by a controller in combination with the curingreaction so as to provide a selected cement viscosity.

Embodiments of the method may further include varying the amount ofenergy applied from the external source in response to a selected lengthof a post-mixing interval. Embodiments of the method may include varyingthe amount of applied energy from the external source in response toambient temperature that is measured by a temperature sensor in thesystem.

Further, embodiments of the method may include varying the appliedenergy from the external source in response to a selected injection rateof the bone cement flow through the system 10. Embodiments of the methodmay include varying the applied energy from the external source so as toprovide a bone cement having an injection viscosity of at least about500 Pa·s, at least about 1000 Pa·s, at least about 1500 Pa·s, at leastabout 2000 Pa·s, at least about 3000 Pa·s and at least about 4000 Pa·s.

In further embodiments the control system may allows for application ofenergy to a bone cement so as to provide a bone cement that possesses asubstantially constant cement viscosity over the selected working time.

In further embodiments the control system 10 may allow for theapplication of energy to a bone cement so as to provide a bone cementthat possesses a plurality of selected time-viscosity profiles of thecement as it exits the injector 100. For example, the controller 145 andenergy emitter 110 may be capable of applying energy to the bone cementin an amount that is sufficient to very rapidly increase the viscosityof the bone cement to a selected viscosity that will inhibitextravasation.

As can be seen in the time-viscosity curve 260 of FIG. 8B, embodimentsof the system 10 and the bone cement 130 discussed herein may beemployed to provide a bone cement whose viscosity can be elevated toabove about 2000 Pa·s within about 15-30 seconds. It may be understoodthat embodiments of the method of bone cement treatment may includeutilizing an energy emitter 110 that applies energy to bone cement tocontrollably increase its viscosity to at least 200 Pa·s, at least 500Pa·s or at least 1,000 Pa·s in less than 2 minutes or less than 1minute. Alternatively, embodiments a method of bone cement treatment mayinclude utilizing an energy emitter that applies energy to bone cementto controllably increase the viscosity to at least 1,000 Pa·s, at least1,500 Pa·s, at least 2,000 Pa·s or at least 2,500 Pa·s in less than 2minutes or less than 1 minute.

In further embodiments, a method of preparing a curable bone cement forinjection into a vertebra may be provided allows a bone cement toexhibit a selected time-viscosity profile. The method may include:mixing bone cement precursors so as to cause a curing reactioncharacterized by a first time-viscosity profile of the bone cement,actuating an energy controller so as to controllably apply energy to thebone cement from an external energy source so as to cause the bonecement to adopt a second time-viscosity profile, different from thefirst time-viscosity profile, and injecting the cement characterized bythe cement second time-viscosity profile into the vertebra. Inembodiments of this method, the cement viscosity may be at least about500 Pa·s, at least about 1000 Pa·s, at least about 1500 Pa·s, at leastabout 2000 Pa·s, at least about 3000 Pa·s, or at least about 4000 Pa·s.Embodiments of the method may further include actuating the controllerto modulate applied energy in response to control signals including, butnot limited to, the length of a cement post-mixing interval, the ambienttemperature, the bone cement temperature, and rate of bone cementinjection into the vertebra.

FIG. 10 provides a schematic, graphical representation of thetime-viscosity response, 250 and 255, respectively, of an embodiment ofthe bone cement of FIG. 8A after mixing at ambient temperatures of about22° C. and 18° C. It can be seen that different levels of energy may beapplied to achieve a similar time-viscosity curve 260 of FIG. 10. Forexample, less energy may be applied to bone cement at about 22° C. thanis applied to the bone cement at about 18° C. in order to achieve thetime-viscosity response 160, as the higher temperature bone cement,prior to energy application, contains more energy than lower temperaturebone cement. Thus, in an embodiment, a method of the present disclosuremay include providing inputs for the control algorithms for controllingapplied energy to cement flows that factor in ambient temperatures.

In one embodiment, the system 10 may be employed in order to provide thebone cement 130 with a working time for polymerizing from an initialstate to a selected endpoint of at least about 10 minutes, at leastabout 12 minutes, at least about 14 minutes, at least about 16 minutes,at least about 18 minutes, at least about 20 minutes, at least about 25minutes, at least about 30 minutes and at least about 40 minutes, asdisclosed in U.S. Provisional Application No. 60/899,487. In anembodiment of the present disclosure, the initial state may include afirst selected viscosity range of the bone cement 130 within about 90 to600 seconds after completion of mixing of the bone cement components. Inanother embodiment of the disclosure, the selected endpoint of the bonecement 130 may include a second selected viscosity range thatsubstantially inhibits bone cement extravasation. Herein, the terms“polymerization rate” and “working time” may be used alternatively todescribe aspects of the time interval over which the cement polymerizesfrom the initial state to the selected endpoint.

As can be understood from FIGS. 1-6, the energy source 140 may also becapable of applying energy to the bone cement 130 via the emitter 110and accelerating a polymerization rate of the bone cement 130 by atleast about 20%, at least about 30%, at least about 40%, at least about50%, at least about 60%, at least about 70%, at least about 80%, atleast about 90% and at least about 95%, as compared to thepolymerization rate achieved absent this application of energy. Inanother embodiment of the present disclosure, the energy source 140 andcontroller 145 may be capable of accelerating the polymerization rate ofthe bone cement 130 to the selected endpoint in less than about 1second, less than about 5 seconds, less than about 10 seconds, less thanabout 20 seconds, less than about 30 seconds, less than about 45seconds, less than about 60 seconds and less than about 2 minutes.

An embodiment of a method of using the system 10 of FIGS. 1-6 to treat avertebra is also provided. The method includes a first operation ofintroducing a cement injector needle into a vertebra. The needle mayinclude a flow channel extending from a proximal injector end to adistal injector end possessing a flow outlet. The method may furtherinclude a second operation of causing a flow of bone cement from a bonecement source through a flow channel in an energy-delivery component andthe injector needle. The method may additionally include applying energyfrom the energy-delivery component to the flow of bone cement so as tocause a change in the setting rate of the cement so as to reach aselected polymerization endpoint. In this method, the applied energy mayaccelerate setting of a bone cement before it exits the flow outlet ofthe injector. The method and the selected polymerization endpoint mayfurther provide a bone cement that exhibits a viscosity thatsubstantially prevents cement extravasation following introduction intothe vertebra.

In an alternative embodiment, referring to FIG. 11, the bone cementsystem 400 may include a first and a second thermal energy emitter forcontrolled application of energy to a bone cement flow within the flowpassageway 112 of the injector system 100. More particularly, firstemitter 110 may be disposed in the first handle component 105 asdescribed previously. A second emitter 410 may be disposed in a medialor distal portion of the second extension component 110 of the injectorsystem 100. The controller 145 may be capable of modulating appliedenergy from the first and second emitters, 110 and 410, to provide acontrolled curing reaction of the flow of bone cement 130. In one methodof use, the first emitter 110 can apply energy to warm the flow ofcement 130 to accelerate it polymerization so that the selected flowrate carries the cement 130 to the location of the second emitter 410 ata viscosity of less than about 500 to 1000 Pa·s and, thereafter, theapplied energy of the second emitter 410 may increase the viscosity ofthe bone cement 130 to greater than about 2000 Pa·s. In this manner, thebone cement viscosity within the flow channel 112 can be kept at a levelthat can be pushed with a low level of pressure and the final viscosityof the cement 130 exiting the outlet 122 can be at a relatively highviscosity, for example, at a level capable of fracturing cancellousbone, such as greater than about 2000 Pa·s.

FIG. 11 further illustrates that electrical connector components 414 aand 414 b may be provided in the interface between the first and secondcomponents, 100 and 105, in order to provide an electrical connectionfrom electrical source 140 to the emitter 410 via electrical wiresindicated at 416 in the handle portion 105 of the system. It may beappreciated that the second emitter 410 can include a PTCR emitter, asdescribed previously, or any other type of heating element. The heatingelement can have any length that includes the entire length of theextension portion 124. In one embodiment, the emitter 110 in handlecomponent 105 has a length of less than about 50 mm and can carry avolume of cement that is less than about 1.0 cc, less than about 0.8 cc,less than about 0.6 cc, less than about 0.4 and less than about 0.2 cc.

In another embodiment of the method, the energy-delivery emitter 110 maybe actuated by the operator from a location outside any imaging field.The cable carrying an actuation switch 212 can be any suitable length,for example about 10 to 15 feet in length (see FIG. 6).

In another embodiment of the method, the energy-delivery emitter 110 maybe actuated to apply energy of at least about 0.01 Watt, at least about0.05 Watt, at least about 0.10 Watt, at least about 0.50 Watt and atleast about 1.0 Watt. In another embodiment of the method, the appliedenergy may be modulated by controller 145. In another embodiment of themethod, the energy source 140 and controller 145 may be capable ofaccelerating the polymerization rate of the bone cement 130 to theselected endpoint in less than 1 second, 5 seconds, 10 seconds, 20seconds, 30 seconds, 45 seconds, 60 seconds and 2 minutes. In anotherembodiment of the method, the energy source 140 and controller 145 maybe capable of applying energy to a bone cement composition 130 foraccelerating the polymerization rate of the bone cement 130 by at leastabout 20%, at least about 30%, at least about 40%, at least about 50%,at least about 60%, at least about 70%, at least about 80%, at leastabout 90% and at least about 95%, as compared to the polymerization rateabsent the applied energy.

In certain embodiments, a method of bone cement injection is alsoprovided. The method includes modulating a rate of bone cement flow inresponse to a determination of a selected parameter of the cement flow.Examples of the selected parameter may include the flow rate of the bonecement. The method of bone cement injection may further include applyingthermal energy to the bone cement and modulating the thermal energyapplication from an emitter in the injector body to the cement flow. Themethod of bone cement injection may further include modulating theapplication of energy in response to signals that relate to a selectedparameter, such as the flow rate of the cement flow.

In another embodiment, a method of bone cement injection is provided.The method includes (a) providing a bone cement injector body carrying aPTCR (positive temperature coefficient of resistance) material in a flowchannel therein, (b) applying a selected level of energy to a bonecement flow traveling through the PTCR material, and (c) utilizing analgorithm that processes impedance values of the PTCR material in orderto determine the bone cement flow rate. The method of bone cementinjection may further include modulating a cement injection parameter inresponse to the processed impedance values. Examples of the cementinjection parameter may include, but are not limited to flow rate,pressure, and power applied to the flow.

In a further embodiment, a method of bone cement injection is provided.The method may include: (a) providing a bone cement injector bodycarrying a PTCR material or other thermal energy emitter in a flowchannel therein, (b) causing a bone cement to flow through the flowchannel at a selected cement flow rate by application of a selectedlevel of energy delivery to the cement flow through the emitter, and (c)modulating the selected flow rate and/or energy delivery to maintain asubstantially constant impedance value of the emitter material over acement injection interval. The selected cement injection interval caninclude at least about 1 minute, at least about 5 minutes, at leastabout 10 minutes, and at least about 15 minutes.

In another embodiment of the present disclosure, the method may modulatethe selected flow rate and/or energy delivery to maintain asubstantially constant viscosity of bone cement ejected from theinjector over a selected cement injection time interval. The timeinterval may include from about 1 minute to 10 minutes. The system andenergy source may be capable of applying energy of at least 0.01 Watt,0.05 Watt, 0.10 Watt, 0.50 Watt and 1.0 Watt. In another embodiment, theenergy source 140 and controller 145 may be capable of accelerating thepolymerization rate of the bone cement to a selected endpoint in lessthan about 1 second, less than about 5 seconds, less than about 10seconds, less than about 20 seconds, less than about 30 seconds, lessthan about 45 seconds, less than about 60 seconds and less than about 2minutes.

Another embodiment of a method of bone cement injection may utilizeembodiments of the systems 10 and 400 as described above. Such methodsmay include (a) providing a bone cement injector body with a flowchannel extending therethrough from a proximal handle end though amedial portion to a distal end portion having a flow outlet, (b) causingcement flow through the flow channel, and (c) warming the cement flowwith an energy emitter in a proximal end or medial portion thereof toinitiate or accelerate polymerization of the cement of the cement flow.The method may further include providing a flow rate of the cement flowthat ranges from about 0.1 cc/minute to 20 cc/minute, from about 0.2cc/minute to 10 cc/minute and from about 0.5 cc/minute to 5 cc/minute.

Embodiments of the above-described method of bone cement injection mayfurther provide a selected cement flow rate to provide a selectedinterval in which the cement flows are allowed to polymerize in the flowchannel downstream from the energy emitter. This method may includeproviding a selected interval of greater than about 1 second, greaterthan about 5 seconds, greater than about 10 seconds, greater than about20 seconds, and greater than about 60 seconds.

The above-described method may also utilize an energy emitter thatapplies energy sufficient to elevate the temperature of the bone cement130 by at least about 1° C., at least about 2° C., and at least about 5°C. The method of bone cement injection may additionally includeutilizing an energy emitter that applies at least about 0.1 Watts ofenergy to the cement flow, at least about 0.5 Watts of energy to thecement flow, and at least about 1.0 Watts of energy to the cement flow.The method may include adjustment of the flow rate of the bone cementflow in intervals by controller 145, or being continuously adjusted by acontroller 145.

In another embodiment of a method of the present disclosure, the bonecement injection system of FIGS. 1-11 may utilize a controller 145 andalgorithms for applying energy to bone cement flows to allow the bonecement 130 exiting the injector to possess a selected temperature thatis higher than the ambient temperature of the injector. This abilityreflects the fact that polymerization has been accelerated, thusreducing the amount of total heat released into bone. More particularly,the method may include injecting a settable bone cement into a boneafter mixing a first component and a second component of the bonecement, thereby initiating a chemical reaction to initiate setting ofthe bone cement, accelerating the polymerization with applied energyfrom an external source, and ejecting the bone cement from an injectorportion positioned in bone. The bone cement, upon ejection, may possessa temperature greater than the temperature ambient the injector. Themethod can further include ejecting the bone cement from a terminalportion of an injector positioned in bone at a temperature of at leastabout 28° C., at least about 30° C., at least about 32° C., at leastabout 34° C., at least about 36° C., at least about 38° C., at leastabout 40° C., at least about 42° C., at least about 44° C., at leastabout 46° C., at least about 48° C., at least about 50° C., at leastabout 52° C., at least about 54° C., at least about 56° C., at leastabout 58° C., at least about 60° C., at least about 62° C., at leastabout 64° C., at least about 66° C., at least about 68° C., at leastabout 70° C., at least about 72° C., at least about 74° C., at leastabout 76° C., at least about 78° C., and at least about 80° C.

In another embodiment, a method of injecting a bone cement into bone isprovided. The method includes mixing first and second bone cementcomponents, thereby causing an exothermic chemical reaction whichresults in a thermal energy release. The method may further includeactuating an injector control system capable of controlling thetemperature of the bone cement before the bone cement contacts bone. Ingeneral, the actuating step can include (i) controlling the flow rate ofthe bone cement within a flow passageway of an injector system, (ii)controlling the application of energy to the bone cement from an emitteroperatively coupled to an energy source, and (iii) controlling thedriving force applied to the flow of bone cement which may benefit fromadjustment based on the bone cement viscosity.

The actuating step can also include sensing an operating parameter ofthe bone cement flow to which the controller is responsive. Theoperating parameter can include the bone cement flow rate, the bonecement temperature, the driving force applied to the cement flow, theenergy applied to the cement from an emitter coupled to an energy sourceand cement viscosity and environmental conditions, such as temperatureand humidity in the environment ambient to the injector system. Thus,the controller 145 can be capable of modulating the flow rate,modulating the applied energy, and/or modulating the driving force inresponse to sensing any one or more of the above operating parameters.

In another embodiment, a method of injecting a bone cement is provided.The method includes mixing a first and a second bone cement componentsso as to cause an exothermic chemical reaction that results in a thermalenergy release. The method also includes actuating an injector controlsystem which is capable of controlling an amount of thermal energyreleased from the cement before the bone cement contacts bone tissue tothereby reduce the thermal energy released into the bone.

The thermal energy released from the cement may be directly related tothe level of polymerization acceleration from the applied energy, aswell as the dwell time of the cement within the flow channel before thecement exits the outlet in a terminal portion of the injector. The dwelltime of the cement in the flow channel can be controlled by controller145 as described above, where at least one of the flow rate and drivingforce applied to the cement flow can be modulated. In embodiments of thesystem 10 of FIGS. 1-6, the application of energy by emitter 110 incomponent 105 provides for a dwell time within the flow channel 112before exiting outlet 122 for a flow interval of at least about 5seconds, at least about 10 seconds, at least about 20 seconds, at leastabout 30 seconds, at least about 40 seconds and at least about 60seconds. This method of conditioning and injecting bone cement can allowa thermal energy release from the bone cement before the bone cementcontacts bone of at least about 10%, at least about 15%, at least about20%, at least about 25%, at least about 30%, at least about 35%, atleast about 40%, at least about 45% and at least about 50% of the totalthermal energy released during curing of the bone cement composition.

In another embodiment, it can be understood that the systems and methodsdisclosed herein may be further employed in order to control the amountof thermal energy released from the bone cement before the cementcontacts bone tissue to thus reduce the amount of thermal energyreleased into the bone.

For example, in one embodiment, a method of injecting a bone cementcontrols the amount of thermal energy released by the bone cement beforethe bone cement contacts bone tissue. The method includes controlling aninjector control system that is capable of controlling the rate ofchemical reaction before the bone cement contacts bone tissue. Thereaction rate can be adjusted by the controller such that the maximumcomposition temperature is reached when the cement is within the flowchannel of the injector system, prior to reaching the bone tissue.Beneficially, in this manner, the amount of total thermal energyreleased by the bone cement is released while the bone cement is stillwithin the flow channel of the injector system, before the bone cementcontacts the bone tissue. This method substantially reduces the amountof thermal energy which is released by the bone cement into the bonetissue.

In another embodiment, a method of injecting bone cement includes anactuating step that can include allowing at least about 10% of the totalthermal energy released from a bone cement to be released while the bonecement flows within the injector system. In certain embodiments, suchenergy release may be accomplished by providing a mean cement flow rateof at least about 0.1 cc/min, at least about 0.5 cc/min, at least about1.0 cc/min, at least about 1.5 cc/min, at least about 2.0 cc/min and atleast about 2.5 cc/min during heating within the bone cement injector.The method may further include maintaining the bone cement within thecannula for at least about 20 seconds after being heated.

In another embodiment of the method of injecting bone cement, theactuating step can allow at least about 10% of the total thermal energyreleased from a bone cement to flow over a flow distance within the flowchannel 112 of the injector system, of least 5 mm, at least 10 mm, atleast about 20 mm, at least about 30 mm, at least about 40 mm, at leastabout 50 mm, at least about 60 mm, at least about 70 mm, at least about80 mm, at least about 90 mm and at least about 100 mm.

In certain embodiments of the methods described above to apply energy toa selected volume of a bone cement mixture, a selected amount of thermalenergy from the exothermic reaction of the bone cement components may bereleased within the flow channel so as to inhibit a selected portion ofthe thermal energy from reaching a patient's bones. Beneficially, inthis manner, a reduction in the thermal effects in the bone due tointroduction of the bone cement within the bone may be achieved.Embodiments of the method can include selecting first and second bonecement components, or precursors, that result in a peak temperature ofthe bone cement composition during curing of less than about 75° C.,less than about 70° C., less than about 65° C., and less than about 60°C. Embodiments of such bone cements may include those bone cementsdescribed herein.

Thus, from the above disclosure, it can be understood that, in anembodiment, a bone cement injection system of the present disclosureincludes first and second bone cement components, or precursors, that,upon mixing, result in a chemical reaction that sets the cement mixture.The bone cement injection system further includes an injector systemthat may include a drive system for inducing the cement mixture to flowthrough the system and into bone. The bone cement injection system mayfurther include an energy emitter for applying energy to the cementmixture in the injector system to thereby accelerate the chemicalreaction between the first and second bone cement components therein.The bone cement injection system may also include a controller,operatively coupled to at least one of the drive system and energyemitter, for controlling the acceleration of the chemical reaction inthe bone cement. In one embodiment, the first and second bone cementcomponents, or precursors, may possess a post-mixing peak temperature ofless than about 75° C., less than about 70° C., less than about 65° C.and less than about 60° C. The drive system and the controller mayfurther be capable of controllably applying a driving force to thecement mixture in the injector system of at least about 500 psi, atleast about 1,000 psi, at least about 1,500 psi, at least about 2,000psi, at least about 2,500 psi, at least about 3,000 psi, at least about3,500 psi, at least about 4,000 psi, at least about 4,500 psi and atleast about 5,000 psi.

In one embodiment, the drive system and controller may be capable ofcontrollably maintaining a substantially constant flow rate of thecement mixture. Examples of the flow rate control may include, but arenot limited to, flow rate variations that are within less than about 1%variation; less than about 5% variation; less than about 10% variationand less than about 15% variation.

In one embodiment, the drive system and controller may be capable ofcontrolling a mean cement mixture flow rate. The mean cement flow ratemay include at least about 0.1 cc/min, at least about 0.5 cc/min, atleast about 1.0 cc/min, at least about 1.5 cc/min, at least about 2.0cc/min and at least about 2.5 cc/min. The energy emitter and controllermay further be capable of controllably applying energy to the cementmixture. In certain embodiments, controller may provide at least about20 joules/cc, at least about 40 joules/cc, at least about 60 joules/cc,at least about 80 joules/cc, at least about 100 joules/cc, at leastabout 120 joules/cc, at least about 140 joules/cc, at least about 160joules/cc, and at least about 180 joules/cc of the bone cement.

In a certain embodiment, the bone cement injection system may include anenergy emitter and controller capable of providing a dynamic or apre-programmed adjustment of applied energy to the cement mixture inresponse to a signal indicative of the flow rate of the cement mixture.The signal, in certain embodiments, may include a feedback signal to thecontroller 145 indicative of at least one of the temperature of thecement mixture, the viscosity of the cement mixture, the flow rate ofthe cement mixture and the driving force applied to the cement mixture,at least one environment condition, and combinations thereof.

Further embodiments of the present disclosure relate to bone cementcompositions and formulations for use in the bone cement deliverysystems described above, such as systems 10 and 400. The bone cementformulations may provide extended working times, since the viscosity ofthe bone cement can be altered and increased on demand when injected.

Bone cements, such as polymethyl methacrylate (PMMA), have been used inorthopedic procedures for several decades, with initial use in the fieldof anchoring endoprostheses in a bone. For example, skeletal joints suchas in the hip are replaced with a prosthetic joint. About one millionjoint replacement operations are performed each year in the U.S.Frequently, the prosthetic joint may be cemented into the bone using anacrylic bone cement, such as PMMA. In recent years, bone cements alsohave been widely used in vertebroplasty procedures where the cement isinjected into a fractured vertebra to stabilize the fracture andeliminate micromotion that causes pain.

In an embodiment, a polymethyl methacrylate bone cement may be provided.Prior to injection of the bone cement into a patient, the bone cementmay include a powder component and a liquid monomer component. Thepowder component may include granules of methyl methacrylate orpolymethyl methacrylate, an X-ray contrast agent and a radicalinitiator. Typically, barium sulfate or zirconium dioxide may beemployed as an X-ray contrast agent. Benzoyl peroxide (BPO) may furtherbe employed as radical initiator. The liquid monomer component mayinclude a liquid methyl methacrylate (MMI), an activator, such asN,N-dimethyl-p-toluidine (DMPT), and a stabilizer, such as hydroquinone(HQ). Prior to injecting PMMA bone cements, the powder component and themonomer component are mixed and thereafter the bone cement hardenswithin several minutes following radical polymerization of the monomer.

Typical bone cements formulations, including PMMA formulations, used forvertebroplasty have a fairly rapid cement curing time after mixing ofthe powder and liquid components. This allows the physician to not wastetime waiting for the cement to increase in viscosity prior to injection.Further, the higher viscosity cement is less prone to unwantedextravasation, which can cause serious complications. The disadvantageof such current formulations is that the working time of the cement, thetime during which the cement is within a selected viscosity range thatallows for reasonably low injection pressures while still being fairlyviscous to help limit cement extravasation, is relatively short, forexample, about 5 to 8 minutes. In one embodiment, the viscosity of thebone cement during the working time may range between approximately 50to 500 N s/m² and may be measured according to ASTM standard F451,“Standard Specification for Acrylic Bone Cement,” which is herebyincorporated by reference in its entirety.

In one embodiment, a bone cement of the present disclosure provides aformulation adapted for use with the cement injectors and energydelivery systems described above, such as systems 10 and 400. Theseformulations are distinct from conventional formulations and havegreatly extended working times for use in vertebroplasty procedures withthe viscosity control methods and apparatus disclosed herein and inco-pending applications listed and incorporated by reference above.

In one embodiment, the bone cement provides a formulation adapted forinjection into a patient's body, where the setting time is about 25minutes or more, more preferably about 30 minutes or more, morepreferably about 35 minutes or more, and even more preferably about 40minutes or more. Setting time is measured in accordance with ASTMstandard F451.

In one embodiment, the bone cement of the present disclosure, prior tomixing and setting, includes a powder component and a liquid component.The powder component may include a PMMA that is about 64% to 75% byweight based on overall weight of the powder component. In thisformulation, an X-ray contrast medium may be further provided in aconcentration less than about 50 wt. %, such as about 25 to 35 wt. %,and about 27% to 32 wt. % based on overall weight of the powdercomponent. The X-ray contrast medium, in one embodiment, may includebarium sulfate (BaSO₄) or zirconium dioxide (ZrO₂). In one embodiment,the formulation may further include BPO that is about 0.4% to 0.8% byweight based on overall weight of the powder component. In anotherembodiment, the BPO is less than about 0.6 wt. %, less than about 0.4wt. % and less than about 0.2 wt. % based on overall weight of thepowder component. In such formulations, the liquid component may includeMMA that is greater than about 99% by weight based on overall weight ofthe liquid component. In such formulations, the liquid component mayalso include DMPT that is less than about 1% by weight based on overallweight of the liquid component. In such formulations, the liquidcomponent may also include hydroquinone that ranges between about 30 and120 ppm of the liquid component. In such formulations, the liquidweight/powder weight ratio may be equal to or greater than about 0.4. Insuch formulations, the PMMA may includes particles having a meandiameter ranging from about 25 microns to 200 microns or ranging fromabout 50 microns to 100 microns.

In certain embodiments, the concentrations of benzoyl peroxide and DMPTwithin embodiments of the bone cement composition may be varied in orderto adjust setting times. Studies examining the influence of bone cementconcentration on setting times (FIG. 12) have demonstrated that, in bonecements comprising BPO and DMPT, increases in BPO and DMPT concentrationincrease the set time of the bone cement. The data further illustratethat, of the two bone cement constituents, BPO may exert a greater rateof effect on set time than does DMPT. Thus, in certain embodiments ofthe bone cement composition, the concentration of BPO, DMPT, andcombinations thereof, may be increased within the ranges discussed aboveso as to increase the setting time of the composition.

The setting time of the cement may also be influenced by applying energyto the bone cement composition. As discussed above, embodiments of theinjector system of FIGS. 1-11 may be capable of delivering energy to thebone cement composition. In certain embodiments, the applied energy mayheat the bone cement composition to a selected temperature.

FIG. 13 illustrates temperature as a function of time from initialmixing for one embodiment of the bone composition so injected. The solidline of FIG. 13 represents the behavior of the bone cement compositionwhen it is not heated by the injector system, referred to as condition1. It is observed that, under condition 1, the composition exhibitsthree regimes. The first regime is low heating rate regime, where thetemperature of the composition increases modestly with time. In thisregime, the composition begins to slowly self-heat due the onset of achemical reaction between at least a portion of its components. Thesecond regime is a high heating rate regime, where the chemical reactioncauses the composition temperature rises sharply. Once the temperatureof the composition peaks, the composition enters a third, coolingregime, during which the temperature of the composition decreases backto room temperature.

The dotted line of FIG. 13 represents the behavior of the compositionwhen it is heated by the injector system, referred to as condition 2. Incontrast to condition 1, four regimes of behavior are exhibited by thecomposition under condition 2. The first, low heating rate regime, thesecond, high heating rate regime, and the third, cooling regime, areagain observed. In contrast with condition 1, however, a new, injectorheating regime, is observed between the first and second regimes. Thisnew regime exhibits a rapid increase in the composition temperature dueto injector heating of the composition. Although the compositiontemperature is observed to peak and fall towards the end of the durationof this regime, the temperature does not fall back to the same level asobserved under condition 1 at about the same time. Therefore, when thesecond, high heating rate regime is entered, the temperature of thecomposition under condition 2 is greater than that under condition 1 andthe composition temperature rises to a peak temperature which is greaterthan that achieved under condition 1.

The setting time of the compositions under conditions 1 and 2 can bemeasured according to ASTM standard F451 and compared to identifychanges in setting time between the two conditions. It is observed thatthe setting time of the composition under condition 1 is approximately38 minutes, while the setting time of the composition under condition 2is approximately 28 minutes, a reduction of about 10 minutes. Thus, byheating the bone cement, the setting time of embodiments of the bonecement composition may be reduced.

From the forgoing, then, it can be appreciated that by varying the BPOand/or DMPT concentrations of the bone cement composition, or by heatingthe bone cement composition, the setting time of the bone cement may beincreased or decreased. Furthermore, in certain embodiments, theconcentration of BPO and/or DMPT in the bone cement may be varied andthe composition may be heated so as to adjust the setting time to aselected value. As discussed above, in certain embodiments, the settingtime is selected to be about 25 minutes or more, more preferably about30 minutes or more, more preferably about 35 minutes or more, and evenmore preferably about 40 minutes or more.

Embodiments of the bone cement composition may further be heated usingthe injector system of FIGS. 1-11 in order to alter the viscosity of thecomposition. FIG. 14 illustrates measurements of viscosity as a functionof time for an embodiment of the bone cement compositions heated totemperatures ranging between about 25° C. to 55° C. It may be observedthat the bone cement at the lowest temperature, about 25° C., exhibitsthe slowest rate of viscosity increase, while the bone cement at thehighest temperature, about 55° C., exhibits the highest rate ofviscosity increase. Furthermore, at intermediate temperatures, the bonecement exhibits intermediate rates of viscosity increase.

From the behavior of condition 1 in FIG. 13, it can be seen that thepeak temperature of the bone cement composition is higher when thecement is heated by the injector system. Furthermore, by adjusting theenergy output of the injector system, the temperature to which the bonecement rises may be varied. Thus, embodiments of the injector system maybe employed to deliver bone cements having selected levels of viscosity.

In one embodiment, a bone cement has a first component comprisinggreater than about 99 wt. % methyl methacrylate (MMA), less than about 1wt. % N,N-dimethyl-p-toluidine (DMPT), and about 30 to 120 ppmhydroquinone on the basis of the total amount of the first component,and a second component comprising a powder component comprising lessthan about 75 wt. % PMMA, less than about 50 wt. % of an X-ray contrastmedium, and benzoyl peroxide (BPO).

In certain embodiments, the composition may further comprise less thanabout 0.4 wt. % (BPO) on the basis of the total weight of the secondcomponent. In further embodiments, the composition may comprise about0.2 to 0.3 wt. % BPO on the basis of the total weight of the secondcomponent. In other embodiments, the second component has less thanabout 0.2 wt. % benzoyl peroxide (BPO) on the basis of the total weightof the second component, or less than about 0.1 wt. % benzoyl peroxide(BPO) on the basis of the total weight of the second component. In sucha formulation, the liquid weight/powder weight ratio may be equal to orgreater than about 0.4.

In one embodiment, the bone cement may include a first monomer-carryingcomponent and a second polymer-carrying component, such as the liquidand powder components discussed above. The bone cement mixture, aftermixing, may be characterized by having a viscosity of less than about500 Pa·s at about 18 minutes post-mixing. The bone cement further can becharacterized as having a time-viscosity curve slope of less than about200 Pa·s/minute for at least about 5 minutes after reaching a viscosityof about 500 Pa·s. The bone cement further can be characterized by apost-mixing time-viscosity curve slope of less than 100 Pa·s/minute forat least about 15 minutes, at least about 16 minutes, at least about 17minutes, at least about 18 minutes, at least about 19 minutes, and atleast about 20 minutes.

In one embodiment, the bone cement includes a first monomer-carryingcomponent and a second polymer-carrying component, such as the liquidand powder components discussed above. Post-mixing, the bone cementmixture may be characterized by a time-viscosity curve having a slope ofless than about 100 Pa·s/minute until to the mixture reaches a viscosityof about 500 Pa·s. In other embodiments, the bone cement, post-mixing,can be characterized by a time-viscosity curve slope of less than about100 Pa·s/minute immediately before the mixture reaches a viscosity ofabout 800 Pa·s. In this context, immediately may refer to a time periodless than about 30 seconds. In other embodiments, the bone cementfurther can be characterized by a time-viscosity curve slope of lessthan about 100 Pa·s/minute immediately before the mixture reaches aviscosity of about 1000 Pa·s. In other embodiments, the bone cementfurther can be characterized by a time-viscosity curve slope of lessthan about 100 Pa·s/minute immediately before the mixture reaches aviscosity of about 1500 Pa·s.

In other embodiments, the bone cement further can be characterized by atime-viscosity curve slope of less than about 200 Pa·s/minuteimmediately before the mixture reaches a viscosity of about 500 Pa·s. Inother embodiments, the bone cement further can be characterized by atime-viscosity curve slope of less than about 200 Pa·s/minuteimmediately before the mixture achieves a viscosity of about 1000 Pa·s.In other embodiments, the bone cement further can be characterized by atime-viscosity curve slope of less than about 200 Pa·s/minuteimmediately before the mixture achieves a viscosity of about 1500 Pa·s.In other embodiments, the bone cement further can be characterized by atime-viscosity curve slope of less than 200 Pa·s/minute immediatelybefore the mixture achieves a viscosity of about 2000 Pa·s, about 3000Pa·s and about 4000 Pa·s.

In one embodiment, the bone cement may include a first monomer-carryingcomponent and a second polymer-carrying component, such as the liquidand powder components discussed above. In certain embodiments,post-mixing, the mixture may be characterized by a time-viscosity curvehaving a rate of change of less than about 20% over an interval of atleast about 5 minutes, at least about 10 minutes, at least about 15minutes, and at least about 20 minutes. In other embodiments, themixture may be characterized by a time-viscosity curve having a rate ofchange less than about 40% over an interval of at least about 5 minutes,at least about 10 minutes, at least about 15 minutes, and at least about20 minutes.

In one embodiment, the bone cement may includes a first monomer-carryingcomponent and a second polymer-carrying component, such as the liquidand powder components discussed above. In certain embodiments, aftermixing, the mixture of the first and second components may becharacterized as having a viscosity of less than about 100 Pa·s at about10 minutes post-mixing, less than about 200 Pa·s at about 15 minutespost-mixing, or less than about 500 Pa·s at about 18 minutespost-mixing.

In one embodiment, the bone cement may include a first monomer-carryingcomponent and a second polymer-carrying component, such as the liquidand powder components discussed above. In certain embodiments, aftermixing, the mixture may receive applied energy of at least about 20joules/cc, at least about 40 joules/cc, at least about 60 joules/cc, atleast about 80 joules/cc, at least about 100 joules/cc, at least about120 joules/cc, at least about 140 joules/cc, at least about 160joules/cc, and at least about 180 joules/cc without substantiallysetting in an interval of less than about 10 minutes. In otherembodiments, the bone cement, after mixing, may possess a viscositygreater than about 500 Pa·s within about 10 seconds, about 30 seconds,about 60 seconds, about 90 seconds, about 120 seconds, about 180seconds, and about 240 seconds of application of energy from an externalsource of at least about 60 joules/cc.

In another embodiment of the present disclosure, the bone cementformulation described above may include first and second cementprecursors, such as the liquid and powder components discussed above. Incertain embodiments, the cement mixture of the precursors may becharacterized by a post-mixing interval in which viscosity is betweenabout 500 Pa·s and 5000 Pa·s, and in which the change of viscosity ofless than about 30%/minute. In another embodiment, the settable bonecement includes first and second cement precursors, where the cementmixture of the precursors is characterized by a post-mixing interval inwhich the viscosity of the mixture is between about 500 Pa·s and 2000Pa·s, and in which the change of viscosity of the mixture is less thanabout 20%/minute.

In another embodiment, the settable bone cement includes a firstmonomer-carrying component and a second polymer-carrying component, suchas the liquid and powder components discussed above. In certainembodiments, after mixing the first and second components, the mixtureis characterized by a change of viscosity of less than 20%/minute for atleast three minutes after reaching about 500 Pa·s, about 1000 Pa·s,about 1500 Pa·s, and about 2000 Pa·s.

In another embodiment, the cement includes a first monomer-carryingcomponent and a second polymer-carrying component, such as the liquidand powder components discussed above. In certain embodiments, aftermixing the first and second components, the mixture is characterized bya change of viscosity of less than 30%/minute for at least three minutesafter reaching about 500 Pa·s, about 1000 Pa·s, about 1500 Pa·s, andabout 2000 Pa·s.

In a related embodiment, the cement may includes a firstmonomer-carrying component and a second polymer-carrying component, suchas the liquid and powder components discussed above. In certainembodiments, after mixing the first and second components, the mixtureis characterized by a change of viscosity of less than about 40%/minutefor at least about three minutes after reaching about 500 Pa·s, about1000 Pa·s, about 1500 Pa·s, and about 2000 Pa·s.

In another embodiment, the cement includes a first monomer-carryingcomponent and a second polymer-carrying component, such as the liquidand powder components discussed above. In certain embodiments, aftermixing the first and second components, the mixture is characterized bya change of viscosity of less than 30%/minute for at least five minutesafter reaching about 1000 Pa·s, about 1500 Pa·s, about 2000 Pa·s, about2500 Pa·s, about 3000 Pa·s, about 3500 Pa·s, and about 4000 Pa·s.

In a further embodiment, the cement includes a first monomer-carryingcomponent and a second polymer-carrying component, such as the liquidand powder components discussed above. In certain embodiments, aftermixing the first and second components, the mixture is characterized bya change of viscosity of less than about 40%/minute for at least fiveminutes after reaching about 1000 Pa·s, about 1500 Pa·s, about 2000Pa·s, about 2500 Pa·s, about 3000 Pa's, about 3500 Pa·s, and about 4000Pa's.

In a related embodiment, the cement includes a first monomer-carryingcomponent and a second polymer-carrying component, such as the liquidand powder components discussed above. In certain embodiments, aftermixing the first and second components, the mixture is characterized bya change of viscosity of less than about 50%/minute for at least aboutfive minutes after reaching about 1000 Pa·s, about 1500 Pa·s, about 2000Pa·s, about 2500 Pa·s, about 3000 Pa·s, about 3500 Pa·s, and about 4000Pa·s.

In another embodiment of the present disclosure, a cement includes afirst monomer-carrying component and a second polymer-carryingcomponent, such as the liquid and powder components discussed above. Incertain embodiments, after mixing the first and second components, themixture is characterized by a rate of change of viscosity of less thanabout 50%/minute after reaching a viscosity of about 5000 Pa·s. In arelated embodiment, a cement includes a first monomer-carrying componentand a second polymer-carrying component, such as the liquid and powdercomponents discussed above. In certain embodiments, after mixing thefirst and second components, the mixture is characterized by a rate ofchange of viscosity of less than about 50%/minute after achieving aviscosity of about 4000 Pa·s. In a related embodiment, a cement includesa first monomer-carrying component and a second polymer-carryingcomponent, such as the liquid and powder components discussed above. Incertain embodiments, after mixing the first and second components, themixture is characterized by a rate of change of viscosity of less thanabout 50%/minute after achieving a viscosity of about 3000 Pa·s.

In another embodiment of the present disclosure, a cement includes afirst monomer-carrying component and a second polymer-carryingcomponent, such as the liquid and powder components discussed above. Incertain embodiments, after mixing the first and second components, themixture is characterized by a rate of change of viscosity of less than50%/minute for an interval preceding the point in time the mixtureachieves about 5000 Pa·s, the interval being at least about 2 minutes,at least about 3 minutes, at least about 4 minutes, at least about 5minutes, at least about 6 minutes and at least about 8 minutes.

In a related embodiment, a cement includes a first monomer-carryingcomponent and a second polymer-carrying component, such as the liquidand powder components discussed above. In certain embodiments, aftermixing the first and second components, the mixture is characterized bya rate of change of viscosity of less than about 40%/minute for aninterval preceding the point in time the mixture achieves about 5000Pa·s, the interval being at least about 2 minutes, at least about 3minutes, at least about 4 minutes, at least about 5 minutes, at leastabout 6 minutes, and at least about 8 minutes.

In a related embodiment, a cement includes a first monomer-carryingcomponent and a second polymer-carrying component, such as the liquidand powder components discussed above. In certain embodiments, aftermixing the first and second components, the mixture is characterized bya rate of change of viscosity of less than about 30%/minute for aninterval preceding the point in time the mixture achieves about 5000Pa·s, the interval being at least about 2 minutes, at least about 3minutes, at least about 4 minutes, at least about 5 minutes, at leastabout 6 minutes, and at least about 8 minutes.

In another embodiment of the present disclosure, a cement includes afirst monomer-carrying component and a second polymer-carryingcomponent, such as the liquid and powder components discussed above. Incertain embodiments, after mixing the first and second components, themixture is characterized by a post-mixing interval of at least 4minutes, 6 minutes, 8 minutes or 10 minutes in the interval precedingthe point in time the mixture achieves 3000 Pa·s.

In a related embodiment of the present disclosure, a cement includes afirst monomer-carrying component and a second polymer-carryingcomponent, such as the liquid and powder components discussed above. Incertain embodiments, after mixing the first and second components, ischaracterized by a post-mixing interval of at least about 4 minutes, atleast about 6 minutes, at least about 8 minutes or at least about 10minutes in the interval preceding the point in time the mixture achievesat least about 4000 Pa·s.

In a related embodiment of the present disclosure, a cement includes afirst monomer-carrying component and a second polymer-carryingcomponent, such as the liquid and powder components discussed above. Incertain embodiments, after mixing the first and second components, ischaracterized by a post-mixing interval of at least about 4 minutes, atleast about 6 minutes, at least about 8 minutes or at least about 10minutes in the interval preceding the point in time the mixture achievesabout 5000 Pa·s.

Now turning FIG. 15, embodiments of bone cement described above arecharacterized by their time-viscosity response, cements A and B, andcompared with commercially available cements C, D and E. Cement A is abone cement composition of the present disclosure having a PMMA tomonomer ratio of about 2:1. Cement B is also a cement composition of thepresent disclosure having a PMMA to monomer ratio of about 2.5:1. CementC is Mendec Spine bone cement which includes a PMMA to monomer ratio ofabout 2.1:1. D is DePuy Vertebroplastic cement which includes a PMMA tomonomer ratio of about 2.3:1. Cement E is Arthrocare Parallax acrylicresin, which includes a PMMA to monomer ratio of about 2.4:1.

Cement A includes a first monomer-carrying component and a secondpolymer-carrying component, such as the liquid and powder componentsdiscussed above. In certain embodiments, post-mixing, the mixture ischaracterized by a time-viscosity curve slope of less than about 200Pa·s/minute until the mixture achieves a viscosity of about 3000 Pa·s.In another cement embodiment, Cement A may include a firstmonomer-carrying component and a second polymer-carrying component,where, post-mixing, the mixture is characterized by a time-viscositycurve slope of less than about 200 Pa·s/minute until to the mixtureachieves a viscosity of about 2500 Pa·s. Bone cement B includes a firstmonomer-carrying component and a second polymer-carrying component,where, post-mixing, the mixture is characterized by a time-viscositycurve slope of less than about 200 Pa·s/minute for at least about 20minutes, at least about 25 minutes, and at least about 30 minutes.

Beneficially, as compared to the prior art compositions (C, D, E) eachof compositions A and B may be observed to exhibit a relatively longworking time before their slope increases significantly. Furthermore,compositions A and B exhibit a more linear slope than the prior artcompositions, which indicates that the rate of viscosity change withtime is more constant.

In another embodiment of the present disclosure, a settable or curablebone cement is provided that includes two mixable components asdescribed above: a liquid monomer component and a non-liquid component.In this embodiment of bone cement, the non-liquid component may includepolymer beads or particles containing an initiator, for example, BPO.The non-liquid component may be capable of providing controlled exposureof the initiator to the liquid monomer over a selected time intervalduring which the bone cement sets, also referred to as a settinginterval of the bone cement. The controlled exposure of the initiator,such as BPO, to the monomer, can provide control over the time-viscositycurve of a bone cement over a working time of the cement.

Embodiments of cement may be used with the system of FIGS. 1-11 or maybe used in a conventional form of vertebroplasty. Further embodiments ofthe cement may be employed with the system of FIGS. 1-11 in order toprovide any of the physical properties of the cement discussed herein.

In one embodiment, a settable bone cement may include a mixable firstand second components, wherein the first component includes greater thanabout 99 wt. % methyl methacrylate (MMA), and less than about 1 wt. %N,N-dimethyl-p-toluidine (DMPT), about 30 to 120 ppm hydroquinone on thebasis of the total amount of the first component, and wherein the secondcomponent includes a PMMA component that includes less than about 75 wt.% PMMA, less than about 32 wt. % of an X-ray contrast medium; and aselected wt. % of benzoyl peroxide (BPO) on the basis of the totalweight of the second component. More particularly, the PMMA componentmay includes first and second volumes of polymer beads having first andsecond amounts of BPO, respectively.

In one embodiment of bone cement compositions with controlled exposureof BPO, referring to FIG. 16, the desired differential BPO exposure overthe working time of the cement may be provided by polymer beads orparticles and having differing BPO configurations integrated therein.FIG. 16 illustrates first polymer beads 700 of the non-liquid componentwhich have a small diameter and include BPO 704A in a higher densitywhen compared to BPO 704B within second polymer beads 705 of thenon-liquid component of the cement.

In an embodiment, the first polymer beads 700 can have an average crosssection of less than about 100 microns, less than about 80 microns, lessthan about 60 microns, or less than about 40 microns. The first polymerbeads 700 may further include greater than about 0.5 wt. % of BPO, onthe basis of the total weight of the non-liquid component. Stillreferring to FIG. 16, the second polymer beads or particles 705 can havean average cross section of greater than about 40 microns, greater thanabout 60 microns, greater than about 80 microns, and greater than about100 microns, with a less than about 0.5 wt. % of BPO, on the basis ofthe total weight of the non-liquid component. In combination, the firstand second polymer beads or particles 700, 705 may include less thanabout 5.0 wt. % of BPO, on the basis of the total weight of thenon-liquid component.

In another embodiment, the PMMA component includes a first volume ofpolymer beads 700 having greater than about 0.4 wt. % BPO on the basisof the total weight of the PMMA component and the first volume has amean bead diameter of less than about 100 microns. In this embodiment,the PMMA component may include a second volume of polymer beads 705having less than about 0.4 wt. % BPO on the basis of the total weight ofthe PMMA component and the second volume has a mean bead diameter ofgreater than about 100 microns.

In another embodiment, the bone cement may comprise a plurality ofdifferent PMMA beads of differing sizes, each carrying a BPO. The amountof BPO may be varied, as necessary, between the different PMMA beads. Inanother embodiment, the mean BPO amount contained within the pluralityof beads may range from about 0.3 to 0.6 wt. on the basis of the totalweight of the PMMA.

In another embodiment, the PMMA component may include a first volume ofpolymer beads 700 that has greater than about 0.4 wt. % BPO on the basisof the total weight of the PMMA and the first volume of polymer beads200 has a mean bead diameter of greater than about 100 microns. Further,the PMMA component may include a second volume of polymer beads 705having less than about 0.4 wt. % BPO on the basis of the total weight ofthe PMMA component and the second volume of polymer beads 705 has a meanbead diameter of less than about 100 microns.

In another embodiment of bone cement, FIG. 17, the BPO in the non-liquidcomponent may be included in the form of particles 706 of BPO and BPOparticles 704C integrated into polymer particles 708. The BPO particles706 may possess a mean diameter ranging between about 1 to 40 μm and maybe present within the non-liquid component in a concentration rangingbetween about 0.3 to 2 wt. % on the basis of the total weight of thenon-liquid component. The BPO particles 704C within the polymerparticles 708 may possess a mean diameter ranging between about 0.5 to 5μm and possess a concentration ranging between about 0.1 to 2 wt. % onthe basis of the total weight of the non-liquid component.

In another embodiment, the polymer particles 708 can have regions ofdiffering density of BPO 704C. Examples of densities may include, butare not limited to, about 10,000 to 100,000 particles/cm³ of the polymerparticles 708.

In certain embodiments, BPO particles 706 may be further added to thebone cement composition in combination with the polymer particles 708.The BPO particles 706 may possess a mean diameter ranging between about1 to 40 μm and may be present within the non-liquid component in aconcentration ranging between about 0.3 to 2 wt. % on the basis of thetotal weight of the non-liquid component.

In another embodiment of bone cement, FIG. 18, the BPO configuration inthe non-liquid component can include polymer particles 710 comprisinglayers of BPO. The BPO may be configured as a surface layer 714A whichis present on at least a portion of an exterior surface of the polymerparticles 710. In a further embodiment, one or more BPO layers 714B maybe present within the interior of the polymer particles 710. In anadditional embodiment, one or more surface BPO layers 714A may bepresent upon at least a portion of the surface of the exterior surfaceof the polymer particles 710 and one or more interior BPO layers 714Bmay be present within the interior of the polymer particles 710. Theinterior BPO layers 714B may be positioned at radial distances of about5 to 80 μm from the center of the polymer particles 710. The BPO surfacelayers and interior layers 714A, 714B may possess thicknesses rangingbetween about 0.5 to 30 μm. In alternative embodiments, the volume ofBPO surface coatings and interior layers 714A, 714B may range betweenabout 1×10⁻¹⁰ to 1×10⁻⁴ cm³.

In certain embodiments, BPO particles 706 may be further added to thebone cement composition in combination with the polymer particles 708.The BPO particles 706 may possess a mean diameter ranging between about1 to 40 μm and may be present within the non-liquid component in aconcentration ranging between about 0.3 to 2 wt. % on the basis of thetotal weight of the non-liquid component.

In further embodiments, the BPO configuration in the non-liquidcomponent may include a first plurality of polymer particles having BPOdistributed on at least a portion of the surface of the first pluralityof polymer particles and a second plurality of polymer particles havingBPO substantially integrated into or intermixed in at least a portion ofthe second plurality of polymer particles.

In another embodiment of bone cement, the BPO configuration in thenon-liquid component can include polymer particles 716 withmicroencapsulated BPO 712 (see FIG. 19) that is substantially integratedinto the polymer particles 716. These polymer particles 716 may befurther combined with particles 706 of BPO. The BPO particles 706 maypossess a mean diameter ranging between about 1 to 40 μm and may bepresent within the non-liquid component in a concentration rangingbetween about 0.3 to 2 wt. % on the basis of the total weight of thenon-liquid component. In certain embodiments, about 10 to 90% of thetotal BPO content may be integrated into the polymer particles, with theremaining portion of BPO not integrated into the polymer particles. Inother embodiments, about 10-90% of the total BPO content may not beintegrated into the polymer particles, with the remaining portion of BPOintegrated into the polymer particles.

In other embodiments, the BPO configuration in the non-liquid componentmay include particles of BPO integrated into polymer particles andparticles of BPO that are not integrated into polymer particles (e.g.,BPO particles 706). For example, in certain embodiments, about 10 to 90%of the total BPO content may be integrated into the polymer particles,with the remaining portion of BPO not integrated into the polymerparticles. In other embodiments, about 10-90% of the total BPO contentmay not be integrated into the polymer particles, with the remainingportion of BPO integrated into the polymer particles.

In another embodiment, the BPO configuration in the non-liquid componentcan include a polymer powder or particles 720 with BPO particles 722milled into the powder particles, which can cause such BPO particles 722to substantially adhere to a surface of the polymer power particles (seeFIG. 20). Similarly, radiopacifiers can be milled into the surfaces ofthe polymer powder (see FIG. 20). In certain embodiments, the density ofBPO particles 722 and/or radiopacifiers upon the surface of the polymerparticles 720 may range between about 0.01-0.2 g/cm³.

In another embodiment of bone cement, the liquid monomer component caninclude microencapsulated monomer volumes within a sacrificial capsule(not shown).

In further embodiments, the above disclosed bone cement compositions maybe provided in such a manner that the BPO configuration controls theinitiation, or the rate, of chemical reaction caused by mixing theliquid monomer component and the non-liquid component. Thus, in anembodiment of the present disclosure, controlled BPO exposure mayprovide a lengthened setting interval in which the mixture has aflowability property that prevents unwanted extravasation.

In an embodiment, the BPO may be provided in a configuration such thatthe bone cement composition exhibits a viscosity of at least about 500Pa·s within about 30 to 90 seconds after the liquid and non-liquidcomponents are substantially mixed with one another (e.g., post-mixing).In certain embodiments, of the method composition may achieve aviscosity of at least about 500 Pa·s, at least about 1000 Pa·s, at leastabout 1500 Pa·s and at least about 2000 Pa·s within about 30 secondspost-mixing. In other embodiments of the method, the composition mayachieve a viscosity of at least about 500 Pa·s, at least about 1000Pa·s, at least about 1500 Pa·s, at least about 2000 Pa·s and at leastabout 2500 Pa·s within about 60 seconds post-mixing. In furtherembodiments of the method, the composition may achieve a viscosity of atleast about 500 Pa·s, at least about 1000 Pa·s, at least about 1500Pa·s, at least about 2000 Pa·s and at least about 3000 Pa·s within about90 seconds post-mixing.

In further embodiments, the BPO configurations within bone cementcompositions discussed herein may enable the BPO that is exposed to theliquid component of the bone cement composition to be approximatelyconstant over a selected time interval. In certain embodiments, thistime interval may range between about 2 to 10 minutes. In furtherembodiments, the viscosity of the bone cement composition during thistime interval may be greater than about 1000 Pa·s, greater than about1500 Pa·s, greater than about 2000 Pa·s, greater than about 2500 Pa·s,greater than about 3000 Pa·s, greater than about 3500 Pa·s, and greaterthan about 4000 Pa·s.

In another embodiment, the BPO configuration within bone cementcompositions discussed herein may control the amount of BPO that isexposed to the liquid component of the bone cement composition such thatthe composition exhibits a viscosity of less than about 4000 Pa·s afterabout 20 minutes post-mixing, after about 18 minutes post-mixing, afterabout 16 minutes post-mixing, after about 14 minutes post-mixing, andafter about 12 minutes post-mixing. In another embodiment, thecomposition may achieve a viscosity of less than about 3000 Pa·s afterabout 20 minutes post-mixing, after about 18 minutes post-mixing, afterabout 16 minutes post-mixing, after about 14 minutes post-mixing, andafter about 12 minutes post-mixing. In another embodiment, thecomposition may achieve a viscosity of less than about 2000 Pa·s afterabout 20 minutes post-mixing, after about 18 minutes post-mixing, afterabout 16 minutes post-mixing, after about 14 minutes post-mixing, andafter about 12 minutes post-mixing.

In an embodiment, bone cements having such properties may include amonomer component and polymer component such as those described above.In other embodiments, the bone cements may include a monomer componentand a polymer component, where the polymer component includes a firstvolume of beads having a first average wt. % of benzoyl peroxide (BPO),on the basis of the total weight of the first volume of beads, and asecond volume of beads having a second average wt. % of BPO, on thebasis of the total weight of the second volume of beads. In this bonecement embodiment, the first volume of beads may have an average crosssection of less than about 100 microns, less than about 80 microns, lessthan about 60 microns, or less than about 40 microns. The second volumeof beads may have an average cross section of greater than about 40microns, greater than about 60 microns, greater than about 80 microns,and greater than about 100 microns. In a bone cement embodiment, thefirst volume may have less than about 0.5 wt. % of BPO and the secondvolume may have greater than about 0.5 wt. % of BPO. In another bonecement embodiment, the combined first and second volumes may alsoinclude less than about 5.0 wt. % of BPO or less than about 2.5 wt. % ofBPO on the basis of the total weight of the polymer component. In afurther bone cement embodiment, the combined first and second volumeshave greater than about 0.5 wt. % of BPO or greater than about 1.0 wt. %of BPO. In an additional embodiment, at least a portion of the firstvolume is without BPO or at least a portion of the second volume iswithout BPO.

In another embodiment of the present disclosure, the bone cementincludes a monomer component and polymer component, where the polymercomponent includes beads carrying from about 0.2% and 0.6% of BPO, onthe basis of the total weight of the beads. In certain embodiments, atleast about 80% of the BPO is carried on a first portion of beads havinga mean cross section of greater than about 100 microns, and less thanabout 20% of the BPO is carried on a second volume of beads having amean cross section of less than about 100 microns.

In another embodiment of the present disclosure, the bone cementincludes a monomer component and polymer component, where the polymercomponent includes beads carrying from about 0.2% and 0.6% of BPO, onthe basis of the total weight of the beads. In certain embodiments,about 100% of the BPO is carried on a first portion of the beads havinga mean cross section of greater than about 100 microns, andapproximately no BPO is carried on a second portion beads volume havinga mean cross section less than 100 microns.

In another embodiment of the present disclosure, the bone cementincludes a monomer component and polymer component, where the polymercomponent includes beads of at least one polymeric material. The polymercomponent may include from about 0.2% and 3.0% BPO on the basis of thetotal weight of the beads. In further embodiments, a first portion ofthe beads may carry BPO in a surface coating and a second portion of thebeads may carry BPO integrated into the at least one polymeric material.

In another embodiment of the present disclosure, the bone cement mayinclude a monomer component and polymer component, where the polymercomponent includes beads of at least one polymeric material and fromabout 0.2% and 3.0% BPO on the basis of the total weight of the beads.In certain embodiments, the BPO may be provided in at least two of thefollowing forms: as a surface coating on beads, as BPO particles, as BPOin microcapsules, as BPO particles within beads of a polymeric material,and as BPO in microcapsules within beads of a polymeric material.

In one embodiment, depicted in FIG. 21, the concentration or volume ofBPO available may be characterized in a BPO volume (or BPO surface area)versus time plot. For example, in one embodiment of the bone cementcomposition, the slope of the BPO availability curve 750 over time maybe positive in region 755A, and thereafter the slope may beapproximately zero or substantially flat (region 755B) over at least 4minutes, 6 minutes or 8 minutes. In certain embodiments, the BPOavailability within the positive region 755A may initially be zero andthen reach between about 0.004 g/ml/min to 0.04 g/ml/min. Thereafter,the BPO availability may be substantially constant in the above range.In certain embodiments, the total time over which the BPO availabilityvs. time plot exhibits a slope that is approximately zero in apost-mixing interval can be at least 2 minutes, 4 minutes, 6 minutes, 8minutes and 10 minutes. In another embodiment, BPO availability curvecan be controlled in slope over the post-mixing period to flatten,increase in slope or decrease in slope in either direction bycontrolling the amount of BPO exposed to the monomer.

The BPO availability curve in FIG. 21 can be achieved, in certainembodiments, by integrating BPO into polymer particles as depicted inFIG. 16. Upon mixing liquid monomer with the particles 700 and 705, themonomer would rapidly dissolve the small particles 700 which wouldrapidly increase BPO availability resulting in the slope within region755A, and after the small particles 700 were dissolved, then that largerparticles 705 would dissolve slowly exposing a substantially constantamount of BPO to be wetted by the monomer in region 755B of the curve.

In another embodiment of a method of the present disclosure, a method ofmaking a bone cement composition is provided. The method includesproviding a liquid monomer component and polymer component, the polymercomponent having polymer particles contained therein. The method furtherincludes distributing BPO within the polymer particles so as to providea selected BPO availability (e.g., controlled exposure) to the liquidmonomer component over at least first and second time intervals. Incertain embodiments, the BPO may be selectively exposed to the liquidmonomer over the at least first and second time intervals. In certainembodiments, the BPO availability per second over the first timeinterval is substantially greater than the BPO availability per secondover the second time interval. In an embodiment, the first time intervalmay be at least about 1 minute, at least about 2 minutes, and at leastabout 3 minutes. The first time interval can be less than about 5minutes. In other embodiments, the second time interval may be at leastabout 5 minutes, at least about 10 minutes, at least about 15 minutes,at least about 20 minutes, at least about 25 minutes, at least about 30minutes, at least about 35 minutes, and at least about 40 minutes.

FIG. 22 illustrates another embodiment of volume or concentration ofexposed BPO as a function of time. FIG. 22 illustrates curve 800indicating BPO availability over time, indicating the amount of BPO thatmay be available for exposure to the monomer. The first interval 805Amay fall within a range of between about 0.004 g/ml/min to 0.04g/ml/min. FIG. 22 illustrates the second interval 805B in which the BPOavailability is less than the first interval until the BPO availabilityis diminished as the bone cement reaches a setting point. As can be seenin FIG. 22, the composition exhibits a discontinuity in the BPOavailability curve, which provides the cement with an extended workingtime. A bone cement and BPO availability characterized by FIG. 22 can beprovided by a cement formulation described above, or with the use of BPOparticles 706 as in FIGS. 17-19, or BPO surface coatings as in FIGS. 18and 20. The method can further include mixing the liquid monomercomponent and the polymer component and injecting the mixture into bone.In FIG. 22, the BPO availability curve 806 of a conventional PMMA bonecement in shown.

The method can further include mixing the liquid monomer component andthe polymer component and injecting the mixture into bone. In oneembodiment, the BPO availability can be high for about one to fiveminutes post-mixing in order to accelerate an increase in viscosity, andthen the BPO availability can be lower for about the next 5 to 40minutes as the cement is further polymerizing.

In another embodiment, referring to FIG. 23, bone cement precursors canbe characterized by a BPO availability curve 810 that provides highavailability in a first interval 815A, as in FIG. 22, for up to aboutfive minutes to create a rubberized cement condition suited fornon-extravasating injection into bone. Thereafter, BPO availability canbe reduced to about zero for a second interval 815B of about 1 to 20minutes thus maintaining the cement substantially in the rubberizedcondition for injection without substantial extravasation. Thereafter,BPO availability can be increased to a high level for a third interval815C of from 30 seconds to 5 minutes to cause rapid setting of thecement.

Such a BPO availability curve and resulting cement may be provided byusing a non-liquid component consisting of particles 405 as depicted inFIG. 24. In FIG. 24, the BPO particles 822 are milled on the surface ofparticles of PMMA material 820, similar to that of FIG. 20. A surfacelayer of PMMA material 824 interior of the BPO particles 822 is withoutany BPO. Further interior of the PMMA layer 820A, fragmented particlesof BPO coated PMMA particles 820A, with BPO indicated at 822′ and PMMAmaterial indicated at 820B.

It can be understood that upon exposure to the liquid component inmixing, the monomer is initially exposed to the milled BPO surface 822,wetting the surface and thus providing the high BPO availabilityindicated by the first interval 815A of FIG. 22. Thereafter, the BPOavailability would drop to zero as indicated in second interval 815B ofFIG. 22. During this interval, the monomer would slowly dissolve thelayer of PMMA material 824. At a selected subsequent point in time,depending on the selected thickness of the PMMA layer 824, the monomerwould reach the BPO layer 822′ and thus BPO availability would increaseas shown in third interval 815C of FIG. 22. The packed togetherparticles 820 can separate and all BPO surface areas of these particlesmay then be exposed to the monomer. A bone cement composition thatresults from mixing liquid and non-liquid components as described abovewould then provide a cement composition having a time-viscosity curve840 as shown in FIG. 25, which is superimposed over the BPO availabilitycurve of FIG. 23.

In certain embodiments of this method, the selected BPO availability isprovided by at least two different particles having differing BPOconfigurations therein. In one embodiment, the selected BPO exposure maybe provided by a controlling BPO exposure to the monomer component on atleast a portion of the surface area of the particles. In anotherembodiment, the selected BPO exposure may be provided, at least in part,by particles comprising a mixture of a polymeric material and BPO. Inanother embodiment, the selected BPO exposure may be provided, at leastin part, by particles having a surface coating of BPO. In anotherembodiment, the selected BPO exposure may be provided, at least in partby, microencapsulated BPO. In another embodiment, the selected BPOexposure may be provided by particles having layers of polymericmaterials and BPO.

In another embodiment of a method of the present disclosure, the mixablebone cement may exhibit a selected interval in which the release orexposure of BPO or other initiator is controlled. In this manner, aselected concentration or volume of free BPO within the composition maybe achieved over a selected time interval. In one embodiment, free BPOincludes the volume of BPO, or other initiator, that is available orexposed to the liquid monomer post-mixing.

In one specific formulation of a PMMA bone cement, the solid or powdercomponent of the bone cement may include: PMMA, BPO, and ZrO₂. In oneembodiment, polymethylmethacrylate polymer (PMMA) is present within thebone cement in a concentration ranging between about 45%-55 wt. % on thebasis of the total weight of the powder component. In other embodiments,the concentration of PMMA is about 49.6 wt. %. In other embodiments, theBenzoyl Peroxide (BPO) is present in a concentration ranging betweenabout 0.30-0.80% on the basis of the total weight of the powdercomponent In other embodiments, the concentration of BPO is about 0.40wt. %. In additional embodiments, the concentration of Zirconium Dioxideor Barium Sulfate may range between about 45%-55% on the basis of thetotal weight of the powder component. In another embodiment, theconcentration of Zirconium Dioxide or Barium Sulfate is less than orequal to about 50.0 wt. %.

In this cement formulation, the liquid component of the bone cementincludes Methylmethacrylate (MMA), N, N-dimethyl-p-toluidine (DMPT), andHydroquinone (HQ). In one embodiment, the concentration ofMethylmethacrylate (MMA) may range between about 98.0-99.9 wt. % on thebasis of the total weight of the liquid component. In other embodiments,the concentration of MMA may be about 99.5%. In other embodiments, theconcentration of DMPT may range between about 0.15-0.95 wt. % on thebasis of the total weight of the liquid component. In other embodiments,the concentration of DMPT may be about 0.50%. In other embodiments, theconcentration of HQ may range between about 30-150 ppm on the basis ofthe total amount of the liquid component. In other embodiments, theconcentration of HQ may be about 75 ppm

In embodiments of this cement formulation, the powder PMMA component asdescribed above may include a blend of a plurality of PMMA powdersdistinguished by one or more of PMMA molecular weights, particle sizes,and/or concentrations of BPO contained within the powder.

For example, in one embodiment of the bone cement composition, three (3)PMMA powders, Powders 1, 2 and 3, may be provided. The ratio of amountsof each of powders 1, 2, and 3 may range between about 40 to 50% forpowder 1, 30 to 40% for powder 2, and the remainder comprising powder 3.In one embodiment, powders 1, 2, and 3 are mixed in a ratio of: Powder1=44.28%; Powder 2=36.86% and Powder 3=18.86%.

Powder 1 may include a target particle size having a range of about100-120 μm, for example, about 110 microns. The molecular weight of PMMAof powder 1 may range between about 150,000 to 350,000, for example,about 350,000. Powder 1 may further include about 0.9-1.1 wt. % BPO onthe basis of the total weight of the powder component. In certainembodiments, powder 1 may include about 1.0 wt. % BPO.

Powder 2 may include a target particle size having a range of about70-90 μm, for example, about 80 microns. The molecular weight of PMMA ofpowder 2 may range between about 300,000 to 500,000, for example, about400,000. Powder 2 may further include about 1.1 to 1.3 wt. % BPO on thebasis of the total weight of the powder component. In certainembodiments, powder 2 may include about 1.2 wt. % BPO.

Powder 3 may include a target particle size having a range of about 25to 45 μm, for example, about 35 microns. The molecular weight of PMMA ofpowder 3 may range between about 250,000 to 450,000, for example, about250,000. Powder 3 may further include about 0.0-1.1 wt. % BPO on thebasis of the total weight of the powder component. In certainembodiments, powder 3 may include approximately no BPO.

Although the foregoing description has shown, described, and pointed outthe fundamental novel features of the present teachings, it will beunderstood that various omissions, substitutions, changes, and/oradditions in the form of the detail of the apparatus as illustrated, aswell as the uses thereof, may be made by those skilled in the art,without departing from the scope of the present teachings. Consequently,the scope of the present teachings should not be limited to theforegoing discussion, but should be defined by the appended claims.

What is claimed is:
 1. A bone cement system, comprising: a pre-mixturecomprising: a first monomer-carrying component; and a secondpolymer-carrying component, separate from the first monomer-carryingcomponent, the second polymer-carrying component comprising a pluralityof bead populations that have different mean particle sizes and aninitiator in different amounts, the second polymer-carrying componentcomprising: a first polymer bead population having a first mean particlesize and including the initiator at a first weight percent of the firstpolymer bead population, wherein the initiator is integrated throughoutthe volume of each of the first polymer beads; a second polymer beadpopulation having a second mean particle size smaller than the firstmean particle size and including the initiator at a second weightpercent of the second polymer bead population that is higher than thefirst weight percent, wherein the initiator is integrated throughout thevolume of each of the second polymer; and a third polymer beadpopulation having a third mean particle size smaller than the secondmean particle size and including an initiator at a third weight percentof the third polymer bead population that is lower than the first weightpercent, wherein upon forming a mixture of the first monomer-carryingcomponent and the second polymer-carrying component, differentdissolution rates and the different initiator amounts of the pluralityof bead populations control an availability of the initiator in themixture that is sufficiently low and slow-varying over time, such thatthe temperature of the mixture remains below 75° C. and, after aninitial exposure period post-mixing, a time-viscosity curve sloperemains less than or equal to about 200 Pa·s/minute until the mixturereaches a viscosity of about 2500 Pa·s.
 2. The bone cement system ofclaim 1, wherein post-mixing the mixture is characterized as having atime-viscosity curve slope of less than or equal to about 200Pa·s/minute for at least 5 minutes after reaching a viscosity of about500 Pa·s.
 3. The bone cement system of claim 1, wherein after theinitial exposure period post-mixing, the time-viscosity curve sloperemains less than or equal to about 200 Pa·s/minute until the mixturereaches a viscosity of about 3000 Pa·s.
 4. The bone cement system ofclaim 1, wherein after the initial exposure period post-mixing, themixture has a viscosity of greater than or equal to about 2000 Pa·s atabout 18 minutes post-mixing and substantially before the set time ofthe cement.
 5. The bone cement system of claim 1, wherein after theinitial exposure period post-mixing, the mixture is characterized by achange of viscosity of less than or equal to about 30%/minute for atleast three minutes after reaching about 1000 Pa·s.
 6. The bone cementsystem of claim 5, wherein after the initial exposure periodpost-mixing, the mixture is characterized by a change of viscosity ofless than or equal to about 30%/minute for at least about five minutesafter reaching about 1000 Pa·s.
 7. The bone cement system of claim 6,wherein after the initial exposure period post-mixing, the mixture ischaracterized by a change of viscosity of less than or equal to about30%/minute for at least about five minutes after reaching about 4000Pa·s.
 8. A bone cement system, comprising: a pre-mixture comprising: afirst monomer-carrying component; and a second polymer-carryingcomponent, separate from the first monomer-carrying component, thesecond polymer-carrying component comprising a plurality of beadpopulations that have different mean particle sizes and an initiator indifferent amounts, the second polymer-carrying component comprising: afirst polymer bead population having a first mean particle size andincluding the initiator at a first weight percent of the first polymerbead population, wherein the initiator is integrated throughout thevolume of each of the first polymer beads; a second polymer beadpopulation having a second mean particle size smaller than the firstmean particle size and including the initiator at a second weightpercent of the second polymer bead population that is higher than thefirst weight percent, wherein the initiator is integrated throughout thevolume of each of the second polymer; and a third polymer beadpopulation having a third mean particle size smaller than the secondmean particle size and including an initiator at a third weight percentof the third polymer bead population that is lower than the first weightpercent, wherein upon forming a mixture of the first monomer-carryingcomponent and the second polymer-carrying component, differentdissolution rates and the different initiator amounts of the pluralityof bead populations control an availability of the initiator in themixture that is sufficiently low and slow-varying over time, such thatthe temperature of the mixture remains below 75° C. and a time-viscositycurve slope remains less than or equal to about 200 Pa·s/minuteimmediately before the mixture reaches a viscosity of about 2000 Pa·s.9. The bone cement system of claim 8, wherein the time-viscosity curveslope is less than or equal to about 100 Pa·s/minute before the mixturereaches a viscosity of about 1500 Pa·s.
 10. The bone cement system ofclaim 8, wherein the time-viscosity curve slope is less than or equal toabout 200 Pa·s/minute immediately before the mixture reaches a viscosityof about 1000 Pa·s.
 11. A bone cement system, comprising: a pre-mixturecomprising: a first monomer-carrying component; and a secondpolymer-carrying component, separate from the first monomer-carryingcomponent, the second polymer-carrying component comprising a pluralityof bead populations that have different mean particle sizes and aninitiator in different amounts, the second polymer-carrying componentcomprising: a first polymer bead population having a first mean particlesize and including the initiator at a first weight percent of the firstpolymer bead population, wherein the initiator is integrated throughoutthe volume of each of the first polymer beads; a second polymer beadpopulation having a second mean particle size smaller than the firstmean particle size and including the initiator at a second weightpercent of the second polymer bead population that is higher than thefirst weight percent, wherein the initiator is integrated throughout thevolume of each of the second polymer; and a third polymer beadpopulation having a third mean particle size smaller than the secondmean particle size and including an initiator at a third weight percentof the third polymer bead population that is lower than the first weightpercent, wherein upon forming a mixture of the first monomer-carryingcomponent and the second polymer-carrying component, differentdissolution rates and the different initiator amounts of the pluralityof bead populations control an availability of the initiator in themixture that is sufficiently low and slow-varying over time, such thatthe temperature of the mixture remains below 75° C. and, after aninitial exposure period post-mixing, a time-viscosity curve sloperemains less than or equal to about 200 Pa·s/minute at about 25 minutes.12. The bone cement system of claim 11, wherein after the initialexposure period post-mixing, the time-viscosity curve slope remains lessthan about 200 Pa·s/minute for at least about 5 minutes after reaching aviscosity of about 500 Pa·s.
 13. The bone cement system of claim 11,wherein after the initial exposure period post-mixing, the mixture has aviscosity less than about 200 Pa·s at about 15 minutes post-mixing. 14.The bone cement system of claim 11, wherein after the initial exposureperiod post-mixing, the time-viscosity curve slope remains less thanabout 200 Pa·s/minute for at least about 25 minutes.
 15. The bone cementsystem of claim 11, wherein after the initial exposure periodpost-mixing, the time-viscosity curve slope remains less than about 100Pa·s/minute for at least about 20 minutes.
 16. The bone cement system ofclaim 11, wherein after the initial exposure period post-mixing, thetime-viscosity curve has a rate of change of less than about 40% over aninterval of at least about 20 minutes.
 17. The bone cement system ofclaim 11, wherein the mixture is characterized by a post-mixing intervalin which viscosity is between about 500 Pa·s and about 5000 Pa·s, and inwhich the change of viscosity of less than about 30%/minute within theinterval.
 18. The bone cement system of claim 11, wherein after theinitial exposure period post-mixing, the mixture is characterized by achange of viscosity of less than or equal to about 30%/minute for atleast about three minutes after reaching about 1500 Pa·s.
 19. The bonecement system of claim 11, wherein after the initial exposure periodpost-mixing, the mixture is characterized by a change of viscosity ofless than or equal to about 30%/minute for at least about five minutesafter reaching about 1000 Pa·s.
 20. The bone cement system of claim 11,wherein after the initial exposure period post-mixing, the mixture ischaracterized by a rate of change of viscosity of less than or equal toabout 50%/minute after reaching a viscosity of about 3000 Pa·s.
 21. Thebone cement system of claim 1, wherein after the initial exposure periodpost-mixing, the viscosity of the mixture increases substantiallylinearly until the mixture reaches the viscosity of about 2000 Pa·s. 22.The bone cement system of claim 1, wherein a total amount of theinitiator in the second polymer-carrying component is between about0.30% and about 0.80% of the second polymer-carrying component byweight.
 23. The bone cement system of claim 22, wherein the availabilityof the initiator remains between about 0.004 g/ml/min and about 0.04g/ml/min for at least 6 minutes after the initial exposure period. 24.The bone cement system of claim 1, wherein the temperature remains belowabout 50° C.
 25. The bone cement system of claim 1, wherein the firstmonomer-carrying component comprises methylmethacrylate (MMA) in anamount between about 98.0% and about 99.9% by weight and furthercomprises N,N-dimethyl-p-toluidine (DPMT) in an amount between about0.15% and about 0.95% by weight.
 26. The bone cement system of claim 1,wherein a total amount of polymer chains in the plurality of beadpopulations is between about 64% and about 75% of the secondpolymer-carrying component by weight, and wherein the secondpolymer-carrying component further comprises an X-ray contrast mediumcomprising barium sulfate in an amount between about 25% and about 35%of the second polymer-carrying component by weight.
 27. The bone cementsystem of claim 1, wherein a total amount of polymer chains in theplurality of bead populations is between about 45% and about 55% of thesecond polymer-carrying component by weight, and wherein the secondpolymer-carrying component further comprises an X-ray contrast mediumcomprising zirconium oxide in an amount between about 45% and about 55%of the second polymer-carrying component by weight.
 28. The bone cementsystem of claim 1, wherein a first amount of the first polymer beadpopulation is between about 40% and about 50% of a total weight of theplurality of bead populations, wherein a second amount of the secondpolymer bead population is between about 30% and about 40% of the totalweight of the plurality of bead populations, and wherein a third amountof the third polymer bead population is a remainder of the total weightof the plurality of bead populations.